HUMAN PHYSIOLOGY
MACMILLAN AND CO., LIMITED
LONDON • BOMBAY • CALCUTTA
MELBOURNE
THE MACMILLAN COMPANY
NEW YORK • BOSTON • CHICAGO
DALLAS • SAN FRANCISCO
THE MACMILLAN CO. OF CANADA, LTD.
TORONTO
HUMAN
PHYSIOLOGY
BY
PROFESSOR LUIGI LUCIANI
DIRECTOR OF THE PHYSIOLOGICAL INSTITUTE OF THE ROYAL UNIVERSITY OF ROME
TRANSLATED BY
FRANCES A WELBY
EDITED BY
DR. M. CAMIS
INSTITUTE OF PHYSIOLOGY, UNIVERSITY OF PISA
WITH A PREFACE BY
J. N. LANGLEY, F.R.S.
PROFESSOR OF PHYSIOLOGY IN THE UNIVERSITY OF CAMBRIDGE
IN FOUR VOLUMES
VOL. II.— INTERNAL SECRETION— DIGESTION-
EXCRETION— THE SKIN
MACMILLAN AND CO, LIMITED
ST. MARTIN'S STREET, LONDON
1913
COPYRIGHT
CONTENTS
CHAPTEE I
PAGE
INTERNAL PROTECTIVE SECRETIONS . . '•„ . .1
1. Theory of glandular organs and secretory processes. Historical
development (Malpighi, Ruysch, Haller, J. Miiller). 2. Glands with
no excretory ducts ; their importance as organs of internal secretion.
3. Structure and mode of secretion of thyroid and parathyroid glands.
4. Cachexia thyreopriva after total thyroidectomy in man : analogy with
spontaneous myxoedema and cretinism. 5. " Tetania thyreopriva"
in man. 6. Varying effects of thyroidectomy in various animals.
7. Criticism of hypotheses put forward to explain effects of thyroid-
ectomy. 8. Experimental basis for theory of auto-intoxication resulting
from functional deficiency of thyroids. 9. Thyroid grafts : injection of
thyroid juice and thyroid feeding in therapeutic treatment of cachexia
thyreopriva. 10. Theory of specific functional independence of thyroid
and parathyroids. 11. Specific protective function of pituitary gland
(glandular portipn of hypophysis). 12. Structure of suprarenal bodies
(adrenals) and paraganglia. 13. Clinical observations and physio-
logical experiments on protective function of the suprarenal bodies.
14. Double function of medullary (or paragangliar) and cortical part
of suprarenals. 15. Experimental injection of suprarenal extract.
16. Active principles of suprarenal and paragangliar system (adrenaline,
paragangline). Physiological action. Bibliography.
CHAPTER II
EXTERNAL DIGESTIVE SECRETIONS . . . . .67
1. Structure of salivary glands : cranial and sympathetic inner-
vation. 2. Nervous mechanism of secretion in salivary glands.
3. Cytological changes in secretory epithelium during rest and secre-
tion. 4. Selective activity of salivary glands. 5. Chemical analysis of
salivary glands and the various kinds of saliva. 6. Structure of
pancreas. 7. Innervation and mechanism of its secretion. 8. Pan-
creatic juice. 9. Internal function of the pancreas. 10. Factors
concerned in internal pancreatic secretion. 11. Structure of gastric
mucosa and glands. 12. Innervation. 13. Gastric juice and the cells
which secrete it. 14. Zymogens which give rise to the gastric enzymes.
v
vi PHYSIOLOGY
15. Intestiual glands. 16. Succus entericus. 17. Mechanism of
intestinal secretion. 18. Structure of the liver. 19. Secretion of bile
in digestion and fasting. 20. Influence on secretion of changes in
hepatic circulation. 21. Chemical constituents of bile. 22. Origin
and metabolic activity of hepatic cells. Bibliography.
MECHANICS AND CHEMISTRY OF DIGESTION IN THE MOUTH AND
STOMACH ....... 152
1. Historical. 2. Mastication, insalivation, formation of alimentary
bolus, and saccharification of starch. 3. Mechanism of deglutition.
4. Innervation. 5. Artificial digestion in vitro to determine action of
gastric juice on different food-stuffs. 6. Influence of spleen on gastric
digestion. 7. Natural digestion in the stomach. 8. Effects of total
gastrotomy. 9. Active movements of stomach in gastric digestion.
10. Mechanism of vomiting. 11. Peripheral and central innervation
of stomach. Bibliography.
CHAPTER IV
MECHANICS AND CHEMISTRY OF DIGESTION IN THE INTESTINE . 207
1. Artificial digestion with the three intestinal secretions : pan-
creatic juice, bile, succus entericus. 2. Mechanism of bile-excretion
in the intestine, and iunervation of muscles of common bile-duct.
3. Natural digestion of chyme in small intestine. 4. Putrefactive
processes in the intestine. 5. Effects of extensive resection of small
intestine in animals and man. 6. Peristaltic movements of intestine.
7. Central and peripheral innervation. 8. Post-mortem auto-digestion.
Why it does not occur during life. Bibliography.
CHAPTER V
INTERNAL RESTITUTIVE SECRETIONS . . . .263
1. Gastric absorption. 2. Intestinal absorption. 3. Fate of the
different groups of food-stuffs after absorption. 4. Importance of
living epithelium to absorption of crystalloid substances (salts and
sugars). 5. Absorption of neutral fats in form of soaps ; synthetic
regeneration by epithelium of intestine. 6. Absorption of proteins,
proteoses, and peptone ; synthetic regeneration. 7. Mechanism of
internal secretion of absorbed and regenerated compensation-products.
8. Formation of glycogen (amylogenesis) and glucose (glycogenesis) by
hepatic cells. 9. Hepatic glycogenesis an internal secretion ; regula-
tion by nervous system. 10. Derivation of hepatic and muscular
CONTENTS vii
PAGE
glycogen from carbohydrates of food. 11. Derivation of glycogen
from decomposition of proteins and fats (diabetes mellitus from patho-
logical causes, experimental diabetes from phloridzin and removal of
pancreas). 12. Accumulation of alimentary fat; adipogenesis. 13. Ac-
cumulation and consumption of alimentary protein. 14. Protective
function of intestinal epithelium and liver. Bibliography.
CHAPTER VI
THE INTESTINE AS AN ORGAN OF EXCRETION . . . 343
1. Physical characters and chemical composition of faeces and
intestinal gases. 2. Alimentary residues and waste products in faeces,
while taking food and in fasting. 3. Formation of faecal masses a
function almost exclusively confined to small intestine. 4. Theory of
normal human faeces. 5. Toxidty of faeces. 6. Mechanical and
chemical functions of caecum. 7. Mechanism of defaecation. 8. Inner -
vation. Bibliography.
CHAPTER VII
ORIGIN OF KATABOLIC CONSTITUENTS OF URINE . . .377
1. General characteristics and com position of human urine. 2. Forma-
tion of urea. 3. Formation of uric acid and the purine bodies.
4. Formation of creatine and creatinine. 5. Formation of hippuric
acid and aromatic substances (ethereal sulphates). 6. Formation of
pigments and chromogens (urochrome, urobilin, uroerythrin, indican).
7. Formation of non-nitrogenous organic acids (oxalic acids, lactic
acids, volatile fatty acids). 8. Carbohydrates of normal and patho-
logical urine (glucose, lactose, animal gum, acetone, glycuronic acid).
9. Proteins of normal and pathological urine (serum-albumin, serum-
globulin, fibrinogen, enzymes). 10. Inorganic constituents of urine
(chlorides, sulphates, alkaline and earthy phosphates, carbonates,
ammonium compounds). 11. Toxicity of urine, and uraemia. Biblio-
graphy.
CHAPTER VIII
THE EXCRETION OF URINE . . . . .418
1. Structure of the kidneys. 2. Mechanism of urinary secretion.
Vitalist theory of Bowman ; mechanical theory of Ludwig. 3. Modi-
fication of urinary secretion with variations of normal conditions of circu-
lation in kidneys ; conclusions as to functions of glomeruli. 4. Effect
on renal secretion of alterations caused in the blood by diuretics ;
criticisms of mechanical theory. 5. Experimental data in favour of
vitalist theory ; criticisms. 6. Innervation of kidneys. 7. Modifica-
viii PHYSIOLOGY
PAf:E
tions of epithelial cells of renal tubules during secretory activity and
functional rest. 8. Function of ureters. 9. Mechanism of retention of
urine. 10. Mechanism of micturition. 11. Innervation of bladder.
Bibliography.
CHAPTER IX
THE SKIN AND CUTANEOUS GLANDS .... 480
1. Structure of the skin : continuous desquamation of the stratum
corneum. 2. Coiled sweat glands : sensible and insensible cutaneous
secretion. 3. Chemical substances excreted in perspiration. 4. Inner-
vation of sweat glands. 5. Sebaceous glands and specific formation of
sebum. 6. Mammary glands. 7. Chemical composition of milk. 8. In-
fluence of diet on the secretion of milk. Origin of secretory products.
9. Histological and chemical processes of milk formation. 10. Influence
of nervous system on the milk secretion. 11. Absorption by the skin.
Bibliography.
INDEX OF SUBJECTS . ... 525
INDEX OF AUTHORS7 539
ERRATA
VOL. I
Page 6, bottom line, for "quantitatively" read "qualitatively."
,, 25, line 25, for "cornea" read "stratum corneum."
,, 35, line 3 from below, for "glycerin" read "glycerol."
„ 109, line 27, for "carbon disulphide" read "ammonium sulphide."
„ 127, line 3 from below, for "Connstein" read "Colmstein."
,, 157, heading 3 should precede "Question."
.» !73, fig. 48, last word, for "distend" read "collapse."
,, 219, bottom line, for "rises" read "falls."
,, 238 is mispaged 328.
,, 239, fig. 90, for "Mosso" read "Marey."
,, 333, line 7 from below, for "afferent" read "efferent."
,, 415, line 13, for " inspiratory " read "expiratory."
VOL. II
Page 28, line 1, and page 52, line 5 from below, for " Christiani " read « Cristiani
„ 73, line 10 from below, for " haeraodrometer " read " haemodromouieter "
„ 210, line 6, for " Ch. " read " Cl. " (Bernard).
CHAPTEE I
INTEKNAL PROTECTIVE SECEETIONS
CONTENTS. — 1. Theory of glandular organs and secretory processes. Historical
development (Malpighi, Kuysch, Haller, J. Miiller). 2. Glands with no excretory
ducts ; their importance as organs of internal secretion. 3. Structure and mode
of secretion of thyroid and parathyroid glands. 4. Cachcxia thyreopriva after
total thyroidectomy in man : analogy with spontaneous myxoedema and cretin-
ism. 5. " Tetania thyreopriva " in man. 6. Varying effects of thyroidectomy in
various animals. 7. Criticism of hypotheses put forward to explain effects of
thyroidectomy. 8. Experimental basis for theory of auto-intoxication resulting
from functional deficiency of thyroids. 9. Thyroid grafts : injection of thyroid
juice and thyroid feeding in therapeutic treatment of cacfiexia thyreopriva.
10. Theory of specific functional independence of thyroid and parathyroids.
11. Specific protective function of pituitary gland (glandular portion of hypo-
physis). 12. Structure of suprarenal bodies (adrenals) and paraganglia.
13. Clinical observations and physiological experiments on protective function of
the suprarenal bodies. 14. Double function of medullary (or paragangliar) and
cortical part of suprarenals. 15. Experimental injection of suprarenal extract.
16. Active principles of suprarenal and paragangliar system (adrenaline, para-
gangline). Physiological action. Bibliography.
IN the last chapter (Vol. I. xiv.) we discussed the formation of
lymph through the walls of the blood capillaries, and the physiology
of the lymphoid tissues and organs (which continually pour out
new cells, as well as the chemical products of their anaboHsm and
katabolism, into the lymph and blood stream), and referred in
general terms to the physiological concept of the so-called secretory
processes. If secretion means every alteration by the tissue-cells
of the medium in which they live — either by the removal from
it of all the materials required for their nutrition, or by the
return to it of all the products of their metabolism — we should
obviously have to admit that every living cell, as such, exhibits
secretory activity (Brown-Sequard). But the concept of secretion
must be taken in a more restricted sense. The term secretory
is not applied to the cells which form the nervous and mus-
cular tissues, nor, speaking generally, to the active and passive
mechanisms of sensation and movement, while it is used of the
histological elements that participate actively in the production
and purification of the blood and lymph, particularly the epithelia
VOL. II 1 B
2 PHYSIOLOGY CHAP.
of the tissues and glandular organs. This differentiation between
the two kinds of cells arises from the fact that while in the former
the exchange of materials with the medium (blood and lymph)
is the means, or condition, of the development of other forms of
energy, and is subservient to other special functions, in the latter,
which are known as "secretory," this exchange is the specific
function — hence it is more prominent, and assumes a distinctive
character.
From this point of view the physiological concept of secretion
is entirely independent of the morphological concept of the gland.
In so far as the cells of the lymphoid or adenoid tissues and
organs considered in the last chapter have a lymphapoietic and
haemapoietic function, they are true secretory tissues and organs,
though destitute of glandular structure proper. But they are
intercalated along the lymph- and blood-vessels, with which they
communicate directly, and into which they pour their cytological
and chemical products, while gland, in the widest sense, implies a
complex of secreting epithelial cells, which form the walls of cavities
that are quite distinct from the lymph- and blood-vessels, and in
which the secretion, i.e. the product of their secretory activity,
accumulates.
The physiological study of the adenoid tissues and glands is
thus logically succeeded by that of the glandular tissues and
organs proper.
I. Midway in the eighteenth century, Albrecht von Haller,
speaking of the functions of the glandular organs, observed :
multa in physiologia obscura ; obscurius hac ipsa functione nihil.
So long as the structure of the glandular organs was imperfectly
known, physiological theories as to the secretory processes were
necessarily vague and confused, and highly speculative in
character. To cite a classical example : the ancients long held
that the pituita, or nasal mucus, was a secretion of the brain,
that flowed through the lamina cribrosa of the ethmoid. The
error was only corrected in 1660, when Schneider described the
mucous membrane which bears his name.
At the same period the anatomy of the glands was more
closely studied by Glisson, Wharton, Wirsung, Stensen, Kivini,
Peyer, and Brunner. Malpighi (1665) was the first who
investigated their internal structure. He stated that all the
glandular ducts terminate in acini (grana glandulosa}, which
receive their juices from the minute blood-vessels by which they
are surrounded, and that the juices collected within the acini were
then poured out through the excretory ducts.
Kuysch (1696) disputed this theory, and maintained, on the
strength of fallacious arguments derived from his celebrated
artificial injection of the glandular vessels, that the gland
substance proper is also composed of blood-vessels, and that the
i INTEENAL PEOTECTIVE SECEETIONS 3
finest terminal ramifications of these vessels (where no blood
corpuscles can penetrate) are in direct continuity with the origin
of the excretory ducts.
Haller (1757) decided the controversy between Malpighi and
Euysch in favour of the latter, and tried to re-establish the ancient
doctrine, by which the arteries terminate in the form of open
mouths, either in the excretory ducts, or in the so-called cellular
tissue, in the lymphatic sinuses, the skin, etc. The argument on
which he founded this unfortunate theory (which contradicted
Malpighi's discovery of the capillary vessels as a completely closed
system uniting the arteries with the veins) was the passage of
injection masses, as performed by Euysch, from the blood vascular
system into the excretory ducts of the glands, and the haemorrhages
simultaneously observed in the excretory canals. Haller's
doctrine, based on imperfect morphological data, held its own for
many years, until it was overthrown by the masterly "monograph
of Johannes Miiller, De glandularum secernent ium structura
penitiori (Lipsiae, 1830). Muller's wide anatomical and embryo-
logical observations on the various secretory organs found in the
different classes of vertebrates, laid the foundations of modern
glandular morphology, and from this he deduced the physiological
concepts of his classical treatise. Its most characteristic points
are briefly as follows : —
(a) Whatever differences of structure exist in the glands of
animals and man, they all obey the same laws, and present an
uninterrupted series from the simplest follicle to the most
complex gland.
(6) All glands present internally a large secreting surface,
obtained in an immense variety of forms. In all, however, the
surface extension is due to development of the excretory ducts in
the form of internal cavities or blind canals, as held by Malpighi.
(c) In all glands, the blood capillaries behave in respect to the
walls of the canals and extremities of the glands as to every other
thin secreting membrane. They do not open by orifices into the
secretory spaces or cavities, but form a close capillary network
round them, which unites the dendritic ramifications of the
arteries and veins, as held by Malpighi.
(£?) Secretion is only a particular mode of the metamorphoses
which the blood undergoes in circulating through the organs.
The most complicated gland is but a large surface adapted to
the smallest possible space, -through which transformation of the
blood takes place. Secretion does not occur only at the ex-
tremity of the glandular ducts, in the acini, supposed hypo-
thetically to exist in every gland. Acini, in the sense of closed
vesicles, are present only in a very small number of glands.
Secretion takes place throughout the length of the glandular
canals.
4 PHYSIOLOGY CHAP.
(e) The special characteristics and differences in the secretions
depend not on any external and mechanical change, nor upon
the anatomical form of the gland, but solely upon the specific
character of the living organic substance (epithelium) which
invests the internal secreting ducts. The difference in secretions
depends, therefore,, upon the same cause which determines differ-
ences of conformation and of life of the organs in general : there
is but one difference, i.e. in the one case the altered blood is
incorporated with the organ, in the other it passes beyond its
limits, and appears externally to it, in the form of secretion.
(/) The chemical processes carried out in the secretory organs
are twofold. On the one hand, they serve the nutrition, develop-
ment, or formation of new cells ; on the other, the formation of a
heterologous product of secretion. The secreting cells differ
chemically from the product secreted, although they may contain
a small amount of the latter. Secretion cannot, therefore, be
explained as a simple liquefaction of the pre-existing molecules of
the secretory elements. We must assume that the products of
secretion are gradually perfected in what may be a long journey
through the canaliculi of the gland.
This conception of the general morphology and physiology, of
the secreting glands as formulated by Johannes Mu'ller still holds
good, and is a fitting introduction to the special study of the
functions of the individual organs and mechanisms of secretion.
Subsequent work has supplied a wealth of details, but all are in
harmony with the general doctrine of the great master, which
may be summed up in the statement that what fundamentally
underlies each secretory process is the specific physiological activity
of the living substance by which the secreting surfaces are invested.
After Sehwann had established the Cell Theory in 1839, and
it had been applied by Henle and Kolliker to the physiology of
secretion, the idea of the living substance, as described by Johannes
Miiller in 1830, was more exactly conceived as the living epithelial
cells which clothe the internal cavities and the secreting surfaces.
Eeal knowledge of the intimate secretory processes of the gland
cells only became possible, however, after the progress of
histological technique enabled Heidenhain and his School to form
a morphological comparison between glands in the state of rest,
and those functioning actively.
A more palpable advance in regard to the specific nature of
the secreting cells resulted from the chemical analyses of the
various products of their secretory activity, undertaken by a host of
observers. Advance in this direction has gone pari passu with
that of chemical physiology. Much, however, in regard to the
chemical composition of the secretions still remains incomplete
and imperfect, and what we know at present is little in comparison
with what remains to be learned — except for certain secretions
i INTEKNAL PKOTECTIVE SECEETIONS 5
which it is possible to obtain in large quantities (e.g. urine, milk,
bile), and which have accordingly been the subject of numerous
and exhaustive researches.
The progress of physics again (particularly Dutrochet's theory
of the phenomena of diffusion through permeable membranes, the
kindred phenomena of imbibition, capillarity, nitration, the
modern doctrine of osmosis through semi-permeable membranes,
the molecular concentration of solutions, the isotonicity of animal
fluids) has stimulated physiologists in the task of reducing the
phenomena of secretion as far as possible to common mechanical
principles. In this laudable attempt Ludwig is pre-eminent.
As we shall see, he founded a mechanical theory of renal
secretion that still holds its own in physiological text -books,
and accounts for the fundamental phenomena that accompany the
formation of urine. Generally speaking, however, it must be
admitted that in the actual state of science we are very far from
any mechanical concept of the secretory processes taken as a
whole. All the forces brought into play with this object are
confronted by the enigma of the metabolic activity of the living
cell, so that the teaching of Joh. Miiller stands firmer nowadays,
after all the vigorous attempts that have been made to overthrow
it, than in 1830 when it was first formulated.
II. The simplest glands, from both the morphological and the
physiological point of view, are represented by epithelial tissues,
which form alveoli or perfectly closed spaces, i.e. are destitute of
excretory ducts by which the secretion is poured out either to
the cutaneous surface, or to the inverted mucous surfaces (of the
digestive tube, respiratory passages, genito-urinary apparatus).
Since all external secretion is excluded by the absence of excretory
ducts, it is evident that these closed glands are capable of
internal secretion only. Their secretions collect in the glandular
spaces, and in proportion as they acquire a certain tension pass
through the pores or interepithelial spaces into the periglandular
lymph spaces, or are directly absorbed by the network of blood
capillaries that surrounds the epithelial layer.
These closed glands have therefore a structure and in all
probability a function highly similar to that of the lymphoid
tissues and organs discussed in the last chapter. Morphologically,
they differ only in having epithelial cells as their essential
substrate, while they do not communicate directly, and are not
intercalated along the lymph and blood paths, but form quite
distinct glandular spaces : physiologically, they differ because
they do not contribute to the formation of the primary cytological
and chemical elements of the blood and lymph, but represent
special factors which modify the constitution of these two fluids, so
as to adapt them to the normal life of the body as a whole.
The recognition of the vast importance of the secretory function
PHYSIOLOGY
CHAP.
of this group of glandular organs constitutes one of the finest
achievements of modern experimental physiology. It more par-
ticularly includes the physiology of the thyroid gland, the
parathyroids, the hypophysis or pituitary gland, 'the suprarenal
capsules, the paraganglia; to the same category belong al»
pineal gland, the carotid glands, and the coccygeal gland, ot which
the functional significance is still unknown.
III. The Thyroid Gland (more correctly glandula tliyreoidea
is in man a single organ, in colour dark red shading into yellow,
which lies at the sides and in front of the larynx and the two
first tracheal rings. Two lateral lobes and a median isthmus can
be distinguished, above which rises a slender conical process
(Morgagni's pyramid) which is attached to the thyroid bone by a
• Fio. 1.— A, Human thyroid gland, showing bifurcation of lower end of pyramidal process, one part
going to each ateral lobe. B, the same, with pyramidal process attached to left lobe of
gland; isthmus absent. C, the same, with pyramidal process and isthmus absent. (C. F.
Marshall.)
fibrous and muscular band (Fig. 1, A). It varies considerably
in size, the weight seldom exceeding 30-40 grms. It is generally
more developed in females than in males, and often swells at the
periods of menstruation.
In the cat, rabbit, guinea-pig, and rat, the isthmus joining the
two lobes is represented by a very slender band of thyroid tissue ;
in the dog, on the contrary, the two lobes are almost always
separated, as, by a congenital anomaly, may also occur in man
(Fig. 1, B and C). The isthmus is almost always well developed
in the ape, as also in ruminants.
The thyroid is invested by a transparent capsule of dense
areolar tissue which connects it loosely with the adjacent parts,
and penetrates to the interior, separating the substance into small
lobules -of unequal form and size. When cut into, a yellow,
sticky fluid escapes from the surface, which had previously been
contained in a multitude of closed vesicles or follicles surrounded
i INTEENAL PEOTECTIVE SECEETIONS 7
by areolar connective tissue, and richly provided with blood and
lymph vessels. The size of the vesicles varies considerably; the
largest may be one millimetre in diameter, so that they are
visible to the naked eye. They are rounded or oval in form,
with a wall consisting of a single layer of cubical or columnar
epithelial cells, which are the secreting elements (Fig. 2).
According to Langendorff two kinds of cells can be dis-
tinguished : " Hauptzellen," which have sharp outlines and shin-
ing, finely granulated protoplasm ; " Colloidzellen," which have
indefinite outlines and protoplasm filled with large granules,
shown by their affinity for certain pigments to consist of colloidal
substance. The first are young cells that secrete by exudation ;
FIG. 2. — Thyroid gland of infant. Vesicles of various sizes, lined with single layer of cubical
epithelial cells.
the second are older and exhibit a marked secretory activity,
during which they liquefy and break up, so that both protoplasm
and nucleus pass into the secretion. In fact, the colloid
fluid of the alveoli contains both the old disintegrated epithelial
cells, and leucocytes that have emigrated from the blood
capillaries, as well as erythrocytes in process of destruction and
discoloration.
Llibcke (1902) concluded from histological observations, more
particularly of fresh preparations of the gland, that the so-called
"colloid" cells are only artificial products, due to the diffusion of the
contents of the vesicle in and around the atrophied epithelial cells.
In any case they would not represent the secreting cells. Accord-
ing to this author the thyroid vesicles contain a homogeneous fluid,
which is not shiny, and is quite distinct from the protoplasm,
being watery or gelatinous in consistency. It can be washed out
8 PHYSIOLOGY CHAP,
with water, and coagulates after death, when it resembles the
fixed content of the vesicles.
Lewandowsky (1902) came to the same conclusion from histo-
logical work on the thyroid of dog, cat, rabbit, ape, lamb, and
hedgehog. He found that the secretion from the vesicular
epithelium was quite fluid, and indistinguishable under the
microscope from other protein solutions. According to this, there
are no colloid cells which secrete preformed colloidal substances.
This secretion first assumes the properties of a colloid in the
vesicular lumen.
The blood-vessels, which are numerous and large in proportion
to the size of the organ, penetrate the cavities of the interstitial
connective tissue, where they ramify rapidly, and come into
intimate relations with the walls of the alveoli, round which they
form a capillary network that is in perfect contact with the
epithelium. The lymphatics arise from the spaces of the inter-
lobular and interalveolar connective tissue, forming a number of
large trunks that anastomose into plexuses at the surface of the
organ.
The nerves that supply the thyroid come from the two
laryngeals, superior and inferior, from the vagus, and from the
superior cervical ganglion of the sympathetic. Their mode of
termination in the muscle cells of the vessels and in the epithelial
cells is unknown.
Embryology shows that the thyroid originates from three
epithelial diverticuli of the primitive intestine, two of which form
the lateral lobes, and the third the isthmus and pyramid of
Morgagni. The epithelial cells of the three diverticuli are grouped
into small masses which are then transformed into vesicles or
alveoli. The peripheral cells of each mass constitute the epithelium
of the alveolus ; the central cells become granular, and on breaking
up form the colloidal content of the primitive alveolus.
The primitive epithelial masses are mainly grouped together
to form the principal thyroid gland ; but there are almost invari-
ably certain nodules which do not fuse with it, and which give
rise to small accessory thyroids, — these in the successive phases
of embryonic development may wander to a considerable distance
from their origin and enter into relation with various organs
derived from the cephalic end of the foetus. On a careful compu-
tation of the accessory thyroids found in various places, they
exist in the tongue and in the sub-maxillary, retro-pharyngeal,
retro-oesophageal, laryngo-tracheal, hyoid, crico-thyroid, bronchial,
aortic, and inediastinic regions (D'Aiutolo, 1890). The accessory
thyroids are perfectly similar in structure to the principal thyroid
body, and they also exhibit alveoli filled with colloidal substance,
blood-vessels, lymph spaces and vessels, and nerve filaments.
The Parathyroids (glandulae parathyreoideae] differ completely
INTEENAL PEOTECTIVE SECEETIONS
in structure (as well as function, infra) from the accessory thyroids.
They were first described by Sandstrom (1880) in man and certain
other mammals, externally
to the lateral lobes of the
thyroid body. Subsequent
observations confirmed their
constant presence in mam-
malia, adding to the external
parathyroids other similar
little glands situated on the
mesial surface of the lateral
lobes of the thyroid, the
internal parathyroids, which,
however, may be absent in
certain species (Fig. 3).
In man the outer (also
called the inferior) para-
thyroids lie in front of the
inferior thyroid artery and
the recurrent nerve. Their
position is not constant.
For the most part they are
situated at the inferior \"^°.
angle of the thyroid lobes,
towards the lower part of
the postero-external border,
at a greater or less distance
from it, and closely united
by fine connective tissue.
More rarely they are found at the level of the eighth and tenth
tracheal ring (Fig. 4). It follows that in excising the thyroid body
in man by the subcapsular method, the inferior or outer para-
thyroids are easily left in situ — a fact which, as we shall see, is
of great clinical and physiological importance.
The inner (or superior) parathyroids are situated on the internal
surface, towards the upper pole of the thyroid lobes, with which
they are intimately connected, since they are wrapt in a common
sheath of connective capsular tissue, and sometimes lie in the
depth of the thyroid substance. In surgical thyroidectomy these
must obviously be excised along with the thyroid body.
The structure of the parathyroids (both outer and inner)
differs from that of the principal and accessory thyroids. They
consist not of hollow vesicles, but of compact masses or columns
of epithelium cells, which sometimes anastomose into branching
cords. Between the cell masses there are septa of connective
tissue, which convey the blood-vessels and nerves into the gland
substance (Fig. 5).
Fio. 3. — Transverse section of left lobe of thyroid from
a two-months' kitten. (Kohn.) a, thyroid tissue ;
b, thymic tissue ; p, p', inner and outer para-
thyroids.
10
PHYSIOLOGY
CHAP.
The epithelial cells which form the specific substance of the
parathyroids are columnar or polyhedral in shape; they have a
C
FIG. 4.— Human thyroid and -parathyroid glands. A, from behind; B and C, from in front.
A 1, Superiorjparathyroids ; A 2, inferior parathyroids : B 1 and C 1, inferior parathyroids.
small roundish nucleus which may exhibit karyokinesis. Accord-
ing to Vassale and Generali the cytoplasm of the cells is sometimes
Fio. 5. — Part of external parathyroid of last figure. (Kphn.) of5. Shows epithelial cells arranged
in columns, with intervening septa of connective tissue ; TO, HI, cells in mitotic division.
clear or finely granular and does not stain, sometimes it has coarse
stainable granules. In all probability these represent two different
stages of functional secretory activity.
i INTEKNAL PKOTECTIVE SECKETIONS 11
Livini (1900) showed by histological methods that the para-
thyroids are fundamentally composed of epithelium cells, which
are gland cells proper. These cells elaborate two different
substances ; one, the principal, appears in the form of granules
or masses varying in size, which stain an intense green like
colloid substances with Galeotti's method ; the other, in the
form of minute granules, stains bright red, like the chromatin of
the nucleus. The parathyroid secretion is poured out into the
pericellular lymph spaces, and reaches the blood by way of the
lymphatics.
In certain animals small nodules of adenoid tissue with the
structural character of the thymus gland (Fig. 3) are associated
with the parathyroids, which suggests a common embryological
origin. Livini, however, demonstrated that the cells of these
masses (known as the thymic lobules) are epithelial cells for
internal secretion, rather than lymphoid cells. He found, in
fact, that they produce a substance which completely fills the
thymic lobule, and usually increases its size. These modifications
in the cell mass are attended by serious nuclear disturbances,
which eventually lead to the dissolution of the cells. It is worth
noting that this secretory product gives the- same reaction as the
principal product elaborated by the cells of the thyroid and
parathyroid glands.
According to Prenant and Fusari, the external parathyroids
have a common origin with the thymus, the internal with the
lateral lobes of the thyroid. The mode in which this transfor-
mation of the structure and specific character of the epithelial
cells is effected is unknown. In any case, we must exclude
the idea (which in the abstract appears rational enough, and
which was propounded by Gley) that the parathyroid is merely
embryonic thyroid tissue, which in the course of its develop-
ment may be transformed into the latter. The thyroid and .
parathyroid are two structures specifically distinct in character,
and they cannot be vicariously substituted for one another
(infra).
That both thyroid and parathyroid are secreting glandular
organs, and that the colloidal substance collected in the vesicles is
destined to be absorbed from the interfollicular lymph channels,
has been established by the histological work of Biondi with
Heidenhain (1889), Langendorff (1889), and a long series of other
observers, among whom are Vassale and Brazza, and Galeotti,
in Italy. As early as 1839 King demonstrated on dead bodies
that it is possible by exerting a certain pressure on the thyroid to
express the colloidal content of the vesicles into the lymphatics
that issue from the gland. Kohlrausch (1853) and Baber (1876)
showed under the microscope the presence in the intervesicular
lymph channels of colloid substances similar to that contained
12 PHYSIOLOGY CHAP.
in the vesicle. Later workers have tried by various modes of
staining to determine the nature of the epithelial secretions and
the paths by which the secretion penetrates the lymphatics. In
this connection Langendorff s results are very interesting. He holds
that the protoplasm of the colloid cells degenerates, passing into
the secretion along with the nuclei, and leaving stellar interstitial
spaces between the principal cells, through which the secretion
passes freely into the lymphatics (Fig. 6). When the vesicle is
emptied its epithelial cells close up again, and once more present
a complete cavity, which in its turn forms outlets for the secretion
by the above process. In the lymph channels the secretion is
diluted by gradual admixture with the lymph, which carries it
away to the circulation.
FIG. 6.— A, Segment of thyroid follicle from puppy. (Langendorff.) Treated with Friedlander-Zeiss
osmic-haematoxylin method, homogeneous immersion. Numerous cells are seen in colloid
degeneration, distinguished from the principal cells by their dark colour. B, same preparation.
Superficial view of principal cells and colloid cells. The colloidal cells adhere together to form
a network ; they are attenuated, with occasional nuclei, which are flattened and stain more
deeply than those of the principal cells.
According to Lewandowsky, as stated above, the secretion of
the vesicular epithelium is not the colloidal substance but a
mother substance, from which the colloid is formed. It is, he
says, the mother substance that passes into the lymph or blood
vessels. But the passage of true colloidal substance from the
vesicle into the lymphatics has never been proved, while on the
other hand it is not uncommon for a colloidal substance to form in
the lymph spaces.
There are no glandular spaces in the parathyroids analogous to
the vesicles of the thyroid. We must therefore conclude that the
secretions from the epithelial cells are absorbed in the lymph
channels as fast as they are formed. The observations of Mazziotti
and Capobianco (1899), particularly those on the parathyroids of
the cat, give interesting details in this connection. They find that
the blood-vessels which irrigate the epithelial cells contain a
i INTERNAL PROTECTIVE SECRETIONS 13
number of leucocytes in excess of the normal (as compared with
the erythrocytes), and that perivascular lymph spaces exist round
them, which are often wider than the vessels and show a network
of connective filaments coming from the adventitia. They regard
these perivascular spaces as the outflow of the parathyroid secretion,
masses or lumps of a granulated substance being sometimes noted,
which stain like colloidal substance.
IV. The physiology of the thyroid and the modern conception
of it as a glandular organ of internal secretion, indispensable to
normal life, is derived from surgery. After the introduction of
antisepsis, thyroidectomy was attempted in cases of goitre, and the
effects observed. As early as 1856-57, indeed, M. Schiff, in a series
of experiments on total thyroidectomy in animals, noticed that it
was frequently fatal in dogs after the first week, in guinea-pigs
somewhat later, although death could not be referred to the state
of the wound nor to lesions of the recurrent branch of the vagus,
nor of the cervical sympathetic. But he gave no adequate account
of the phenomena by which death is preceded, and abandoned his
researches, owing probably to the inconstancy of the results, since
he found that rabbits, some rats, a dog, and several guinea-pigs
survived the operation.. It was not till after the publications of
the two Genevese surgeons, Reverdin, and Kocher, a surgeon in
Berne (who in 1882-83 described the effects of total excision of
goitre), that these experiments were repeated. The credit of
directing the attention of physiologists to this important subject
is accordingly due to surgery.
We will first review the phenomena of deficiency of the thyroid
gland, starting with all the best-known surgical cases, which may
be regarded as so many physiological experiments performed on
man.
Patients who have undergone total thyroidectomy, and have
already been discharged from the hospital as cured, experience the
initial symptoms of glandular deficiency either at once or at
latest some weeks after the operation. They feel weak, complain
of heaviness of the limbs, and more or less diffuse dull pains,
particularly in the legs, which may become acute and assume the
character of pains in the bones.
Other more serious symptoms are gradually associated with the
preceding. After four to five months the face and the extremities
swell and become cold, the muscles are torpid, sometimes rigid,
often exhibiting muscular tremors, and are incapable of carrying
out any delicate manual acts with precision. At first the swelling
is variable ; it is more pronounced in the morning than in the
evening, but steadily increases, until it becomes permanent. It is
not ordinary oedema, in which percussion with the finger leaves
a depression ; it is a hard and elastic swelling. It is specially
localised in the hands, feet, and face, where it produces a
14 PHYSIOLOGY CHAP.
characteristic alteration of the countenance. The lower eyelids
are the first to present a sacculated semi-transparent swelling,
which is hard to the touch ; then the infiltration spreads to the
folds of the face, which become smoothed out ; to the nose which
gets rounded ; to the lips which swell, and bulge outwards, saliva
dribbling from them. The features are coarsened and expression-
less like those of a cretin.
The mental functions accord with this appearance, since they
are blunted, so that the patients lose their memory, become deaf,
taciturn, melancholy, self-absorbed, and reply extremely slowly to
questions. They further complain of slight but perpetual head-
ache ; feel an almost constant sensation of cold, which is most
acute at the extremities ; at times they are seized with vertigo,
and may even lose consciousness.
All these symptoms become still further aggravated. The
whole body may grow more bulky from the extension of the
swelling. The skin loses its elasticity, can only be picked up in
large folds, and becomes dry owing to defective capacity for
sweating. The epidermis desquamates in more or less extensive
lamellae, particularly on the hands and feet ; the hair turns grey,
falls out, and gets constantly thinner.
The heart functions weakly, but with ordinary rhythm ; the
pulse is small and thready. Examination of the blood shows
nothing constant; but there is often a more or less pronounced
and progressive oligocythaemia, which undoubtedly contributes to
the characteristic pallor of the skin, this being of the earthy,
yellow-spotted hue peculiar to cretins.
The respiratory rhythm is almost always normal ; the digestive
apparatus functions well, as also the urinary system. The spleen
is not enlarged.
When thyroidectoniy has been performed during adolescence,
one of the most serious effects is the arrest of development. A
boy on whom Sick operated at the age of ten, had at twenty-eight
become a cretin whose height was only 1/27 metres; a similar case
was described by Schmidt ; and the same phenomenon appeared
in a lesser degree on a third person, on whom Julliard operated at
the age of seventeen.
This complex and characteristic syndrome of morbid pheno-
mena, as described by Kocher, is now generally known by the
name of cachexia tliyreo- or strumipriva, i.e. cachexia consequent
on complete ablation of the thyroid gland.
In 1874 Sir William Gull presented to the Clinical Society of
London five cases of a disease which presented a morbid syndrome
closely resembling that of cachexia thyreopriva. In 1878 W. M.
Ord described five other cases of the same disease, to which he
gave the name of myxoedema, derived from the constant symptom
of thickening and swelling of the skin, as manifested especially in
i INTERNAL PROTECTIVE SECRETIONS 15
the face and limbs, which he proved to be due to a pronounced
accumulation of mucin in the subcutaneous connective tissue.
He observed that the disease was accompanied by a shrivelling of
the thyroid, and the destruction of its follicles by proliferation of
the connective tissue ; but he did not suspect that this degenera-
tion of the gland was the internal cause of the myxoedenia. He
further noted the numerous analogies between myxoedema and
cretinism ; but did not regard the latter as dependent on the
alterations of the thyroid.
It was the cousins Reverdin who recognised these relations,
more particularly the great resemblance between the phenomena
of spontaneous myxoedema and cachexia thyreopriva, to which they
gave the name of operative myxoedema. Kocher, on the other
hand, particularly emphasised the points of contact between
cretinism and cachexia thyreopriva. In 75 per cent of the cases,
cretins exhibit goitre with thyroid degeneration ; and in cases in
which there is no goitre, absence of this gland has been noted
(Curling). In many non- goitrous cretins Kocher verified its
absence by palpation, or at least such a diminution in its volume
that it was not perceptible to touch. It is not surprising that
the resemblance between cretinism and cachexia thyreopriva
should be incomplete, seeing that cretinism is a congenital disease,
and is almost always hereditary. But they may legitimately be
grouped together, since in both the disease depends on a defective
or insufficient function of the thyroid gland.
V. Following the initiative of the Swiss surgeons, the excision
of the thyroid in cases of goitre was practised by many, notably
by Billroth in the Vienna clinique. The results differed from
those described by the cousins Reverdin and by Kocher, in that
the morbid syndrome of slowly developing cachexia thyreopriva
was frequently replaced or accentuated by acute phenomena of
" tetany," which usually caused the rapid death of those operated on.
Out of 53 cases of total thyroidectomy for goitre, reported on by
von Eiselsberg in 1890, there were 12 cases of tetany, 8 with fatal
results. In 8 cases operated on by Mikulicz 4 were attacked by
tetany. Since the first 13 cases of tetany collected by Weiss were
all very young women, it seemed as if this complication were
peculiar to females. Subsequently this was found to be erroneous,
cases of tetany having also been observed in' young males by
Kocher, Mikulicz, Hicquet, and Walkowitsch. Tetany is more
frequent in women than in men, because cases of goitre are
notoriously more frequent in females, and the majority of indi-
viduals operated on accordingly belong to that sex.
" Tetania thyreopriva " may appear on the day of operation ;
more frequently it commences on the second, the fifth or sixth, or
at latest on the tenth day after the operation (Weiss). It begins
with muscular cramp which is usually localised in the limbs, and
16 PHYSIOLOGY CHAP.
particularly in the flexor muscles of the hand 'and forearm ; soon,
however, the spasms invade other muscular groups, inducing
lock-jaw, blepharospasm, cramp of the tongue, trachelismus,
opisthotonus.
The tetanic spasms are preceded, accompanied, or followed by
tachypnea and tachycardia, with a concomitant rise of tempera-
ture of 2-3° C. Sometimes the neuro-muscular super-excitation
assumes the form of clonic-tonic epileptoid convulsions, conscious-
ness being retained. This is generally the most serious symptom
of tetania thyreopriva, and sets in shortly before death.
Unlike simple cachexia, post- operative tetany seldom exhibits
sugar or even albumin in the urine.
The course and outcome of tetany varies. It may consist in
one or more severe attacks, leading rapidly to the death of the
patient. In other cases it may be protracted for many days and
even mouths, when less acute attacks are observed from time
to time, which may be followed by the slowly developing pheno-
mena of cachexia thyreopriva. In other cases, again, tetany in a
more or less intense form may appear much later, 3-4 years after
thyroidectomy, when the phenomena of cachexia thyreopriva are
already fully developed.
VI. These grave effects of thyroidectomy in man were the
subject of much discussion and controversy at the Congress of
German surgeons which took place in 1883. The observations of
Reverdin, Kocher, Wolfler, and Bardeleben were confronted with
not a few cases of goitre in which no subsequent morbid symptoms
were apparent. We shall return later to the cause of this
phenomenon. Meantime, experimental confirmation of the great
physiological importance of the thyro- parathyroid system was
not long wanting. The merit of its discovery is due to M. Schiff,
who in 1884 published two Memoirs on the effects of removing
the thyroid bodies in the dog, which indicated the true solution of
this crucial question. Schiff was followed by a host of experi-
menters in Italy, Germany, and France, whose work threw much
light on the subject, though it is still obscure.
Let us first consider the phenomena consequent on total
thyroidectomy in the dog, on which many experiments have been
carried out.
The total extirpation of both thyroid bodies in these animals
produces e fleets no less complex and variable than in man : usually
they present a combination of the phenomena of tetany and of
cachexia thyreopriva. The operation is almost invariably fatal,
after a period varying from 3-4 days to a month. Death more
often occurs between the sixth and tenth days. The fatal issue
is more rapid when acute symptoms of tetany prevail; it is
retarded when the depressing and dystrophic symptoms of
cachexia predominate. The phenomena of the first and second
i INTEENAL PEOTECTIVE SECEETIONS 17
groups, however, combine and succeed each other so variously in
individual cases, that any separate description of them would be
artificial and arbitrary.
Two to three days after the total ablation of the thyro-
parathyroid apparatus, the dogs begin to exhibit signs of depression,
and are sluggish in their movements, with a decided tendency to
remain crouched. They are unwilling to eat (anorexia), swallow
with difficulty (dysphagia), are inclined to vomit, and end by
• absolutely refusing all food. When they try to move, or are
forced to stir themselves, they exhibit characteristic fibrillar
tremors of the muscles of the thighs, shoulders, and back.
These symptoms gradually become aggravated and complex.
The animals appear uneasy, they whine (as if in pain), rub their
noses on the ground or wall, and shake their bodies as if they
itched all over. At the same time, sensibility to painful and
tactile stimuli seems to be objectively diminished or entirely
abolished, while the pressure -sense is retained (Schiff). On the
third or fourth day, more often on the fifth or sixth, trophic
disturbances make their appearance in the skin, due in great
measure to rubbing with diminished cutaneous sensibility. Con-
junctivitis and keratitis next set in, and are first catarrhal and
subsequently become purulent (Gley), if precautions are not taken
by treatment with disinfectants (Lusena).
The muscular tremor becomes continuous ; it is complicated by
rigidity of the extremities, particularly the hind-limbs, in the form
of tonic extension ; twitches or clonic contractions of certain groups
of muscles, particularly in the temporal muscle and the masseters,
tonic contraction of the masticator muscles (lock-jaw), extending
sometimes to the muscles of the back and limbs (opisthotonus),
and assuming the form of true spasms of tetanic convulsions.
The convulsive spasms are not infrequently complicated by
attacks of tachypnea of no long duration, during which there is a
proportionate increase of temperature (Marchesi). Sometimes the
tachypnea is so intense that the respirations can only be counted
by the graphic method (Gley). Not infrequently, at the close of
life, the respiratory rhythm becomes periodic (Cheyne- Stokes
phenomenon), but this does not last long, and is irregular in form.
Along with tachypnea and hyperthermia there is regularly
tachycardia, which may reach maximal intensity (150 beats to the
minute). On the other hand, in the long intervals (sometimes
whole days) in which there are no convulsive phenomena nor
tachypnea, and the animal is in a drowsy, stupid state or in coma,
the temperature may fall gradually to two degrees below normal
(Ughetti), while the cardiac beats also become less frequent than
the normal (Lusena). Investigation of the respiratory gas ex-
changes agrees with this fact, as they are found to be diminished
after thyroidectomy (Baldoni).
VOL. II C
18 PHYSIOLOGY CHAP.
Much work has been done with the object of determining the
changes in the blood after thyroidectomy, but has led to no
concordant results. The number of the erythrocytes and the
amount of haemoglobin diminishes according to some authorities,
according to others it remains approximately invariable. The
quantity of oxygen fixed by the haemoglobin of dethyroidised
dogs may diminish, or remain approximately unaltered, according
to the nature of the pathological phenomena at the moment of
investigation. The isotonic coefficient of the erythrocytes is
somewhat reduced, owing probably to the altered metabolism
(Bottazzi). The proteins of the plasma alter in their qualitative
relations : at first there is a relative diminution of globulins and
increase of serin; later, on the contrary, the serin diminishes,-
while the globulins relatively increase (Ducceschi). This fact
depends probably on the state of almost complete inanition in
which the dethyroidised dog exists, also on the albuminuria
frequently observed in these animals (Herzen), owing to which
a predominating amount of serin passes into the urine.
Coronedi's recent and systematic researches on this albuminuria
have shown it to be a constant phenomenon, although it varies
in intensity. It sometimes precedes the onset of characteristic
symptoms of thyro-parathyroid deficiency, more particularly the
convulsions. It is curious that this albuminuria can as a rule
be detected most certainly by means of Esbach's citro- picric
reagent.
In addition to albuminuria, glycosuria is often seen in
dethyroidised dogs. It usually sets in two days after the opera-
tion (so that it is not the effect of post-operative traumatism),
and lasts, sometimes intermittently, till death (Falkenberg, Gley).
According, however, to the later and more accurate work of
Coronedi, the reducing power of the urine is seldom due to
dextrose. Coronedi and Luzzato further noted in dogs that the
reaction of the urine became alkaline after parathyroidectomy,
owing to the presence of free ammonia.
Such are the principal pathological features exhibited in dogs
after complete ablation of the thyro-parathyroid apparatus. They
present a less acute course than the typical cases of tetany in man,
and a much more rapid course than Kocher's cachexia. This
greater rapidity doubtless accounts for the absence of myxoedema
in dethyroidised dogs, i.e. swelling owing to infiltration with
mucin. In the dogs which, as a rare exception, lived for some
time after thyroidectomy, Tizzoni and Centanni (1890) saw that
trophic phenomena similar to myxoedema did make a tardy
appearance. Coronedi and Marchetti have recently described
two typical cases of experimental myxoedema in such animals,
the psychical decadence being also particularly pronounced.
In thyroidectomy practised on monkeys (which by their greater
i INTERNAL PROTECTIVE SECRETIONS 19
affinity to the human race might a priori be expected to show
a greater likeness in pathological phenomena), Horsley (1885-86)
reproduced and described the psychical decadence, the alterations
in general nutrition, the special oedemas that were described for
man by Reverdin, and which constituted the syndrome of operative
myxoedema. Tetany was occasionally observed in apes as in man,
and rapidly produced the death of the animal.
Fatal effects with phenomena similar to those in dogs were
observed on cats (Schiff, Vassale, and Sacchi) and foxes (Sanquirico
and Orecchia). In some of the herbivora, on the contrary, especially
the rabbit, on which many experiments have been made, no
particular effects were observed (Schiff, Colzi, Tizzoni and Fileti,
Sanquirico and Orecchia, etc.) Later on we shall examine the
reason for these negative results, as also for the rare survival of
dethyroidised dogs, as noted by Albertoni and Tizzoni, H. Munk,
and others. Thyroidectomy in birds yielded varying results to
Moussu, negative results to Allara and Ewald. In reptiles and
amphibia, on the contrary, the physiological importance of the
thyroid apparatus was evident. The salamander usually died
after a week (Grley, Phisalix, Nicolas). Lizards and snakes
perished in 3-4 weeks (Cristiani).
VII. After this description of the phenomena, the first question
to determine is whether the complex pathological effects observed
after ablation of the thyroid bodies are really the direct con-
sequence of loss of function in the glandular organ, or the indirect
effects of the operation performed on man and other animals. We
will shortly review the principal opinions in regard to this
subject.
Prior to the observations of the cousins Reverdin and of
Kocher on man, which were confirmed by Schiff for other animals,
there was no really scientific theory of the specific function of the
thyroid body. The current hypotheses were more or less gratuitous,
or founded upon superficial observations. Among many such
(which need not be recorded) was that formulated by Schreger
(1791), which had a certain objective foundation. In view of the
situation of the gland between the heart and brain, of the large
arterial vessels with which it is provided, and of their origin in
the arteries that carry the blood to the brain, he opined that the
thyroid functioned as an organ for regulating the circulation in
the upper part of the body, particularly in the brain : ffaec
glandula sanguinis immodicos appulsus a cerebro aderceat et
moderetur. Rush (1806) supported this hypothesis, and explained
the greater development of the thyroid in women by their greater
predisposition to emotion, which is associated with cardiac ex-
citement. The same doctrine was taken up more vigorously
by Liebermeister (1864), who attempted to bring out the great
importance of the regulatory mechanism represented by the
20 PHYSIOLOGY CHAP.
thyroid, in all cases in which there is danger of plethora or
cerebral anaemia. In the first case, by dilatation of its vessels,
the thyroid receives the excess of blood which would otherwise
reach the brain ; in the second, by contraction of its arteries, it
determines a greater flow of blood to the cerebrum. Guyon (1868)
adopted a more complicated, but analogous point of view, affirm-
ing that every increase in cerebral blood-pressure produces an
augmentation in the volume of the thyroid (probably by passive
vascular dilatation) which causes compression of the carotids,
and prevents the blood from flowing in large quantities to the
brain. Finally, Meuli (1884) attempted to give an experimental
basis to the Schreger-Liebermeister theory, demonstrating by a
series of measurements upon himself that the circumference of
the neck varies considerably with the position of the body, these
variations being maximal at the level of the thyroid region.
Without denying whatever may be true in this theory, as put
forward by Liebermeister, its importance must not be exaggerated.
It is obvious that any regulatory or compensatory influence on
the cerebral circulation which may be attributable to the thyroid
arteries can have nothing to do with the specific function of the
thyroid as a glandular organ of internal secretion.
The cousins Keverdin and Kocher (1883), who, as we have seen,
were the pioneers of research into the physiology of the thyroid
as a glandular organ, were not happy in their first attempt to
explain tetany and cachexia thyreopriva in man. According to
Keverdin, this characteristic syndrome depended on disturbances of
innervation caused by lesions of the nerve trunks in the course
of extirpating the thyroid organ. According to Kocher, on the
contrary, the ligation of the great thyroid vessels in excision of
this body produced on the one hand a considerable diminution
in the lumen of the trachea, owing to deficient irrigation by the
blood stream, on the other, a disturbance of the cerebral circulation
by suppression of the thyroid system. The constriction of the
trachea diminished the respiratory gas-exchanges, and indirectly
produced anaemia, leucocytosis, cretinism, coma ; the disturbance
of the cerebral circulation (according to Liebermeister's theory)
caused the convulsions, tachypnea, and tachycardia.
After Schiffs publications (1884) these hypotheses, which, as
we shall see, were reared on an unstable basis, were abandoned
even by their authors. According to Schiff the grave symptoms
consequent on thyroidectomy are the direct consequences of
deficiency of thyroid function, i.e. of the internal secretion of
substances of unknown nature, which are of great importance in
the normal nutrition of the nervous system. When deprived of
these substances of thyroid origin the nervous system becomes
disordered in its functions, and gives rise to the phenomena of
tetany and cachexia thyreopriva. Schiff proved that the extirpa-
i INTERNAL PROTECTIVE SECRETIONS 21
tion of one thyroid only was innocuous in the dog. On the other
hand, he found that if the thyroid of one dog were grafted into
the peritoneal cavity of another, and the two thyroids of the latter
extirpated after a considerable period, the pathological phenomena
were delayed, and the animal survived the operation longer. He
observed that, generally speaking, the grafted thyroid did not take
root, but was absorbed after a certain time. He explained the
protracted survival of the animals on the assumption that during
the disintegration of the thyroid introduced into the peritoneum,
the substances necessary to the normal nutrition of the nervous
system are absorbed and carried to the circulation. He con-
jectured that the same effect could be obtained by the periodic
injection of thyroid juice into a dethyroidised animal, — as was
subsequently demonstrated by other experimenters.
Another important fact stands out in Schiff's memoir. He
states that if both thyroids in a dog are excised in two successive
operations, at about a month's interval, no pathological symptoms
appear in the animal. With a less interval between the two
operations, the fatal symptoms are delayed; if the interval is
reduced to one week they invariably set in. This suggested to
Schiff the hypothesis that in the interval between the first and
second thyroidectomy the activity of another organ, similar to or
identical in function with the thyroid, might be progressively
exaggerated, so as to act vicariously for the excised thyroid. The
presumptive existence of another organ functioning vicariously for
the thyroid, explains, he says, why total thyroidectomy in certain
animals, e.g. rabbits and rats, and on rare occasions dogs also, may
be innocuous. Later on we shall examine the value of this
hypothesis. Meantime it may be stated that the fundamental
fact on which it is based was immediately contradicted by the
experiments of Sanquirico and Canalis (1884-85), who constantly
obtained fatal results from the removal in two operations of both
thyroids in dogs, whatever the period between the first and second
operation. They also observed another enigmatical fact, the
importance of which will appear below. Removal of the upper half
of both thyroids is fatal in the dog, while removal of the two
lower halves is innocuous.
Immediately after Schiff's publication, Colzi proposed that
these experiments upon the thyroid should be repeated in our
laboratory in Florence, in order to see, from an exclusively
surgical standpoint, which minimal portion of the organ it was
necessary to preserve in dogs in order to avoid the phenomena of
"tetania thyreopriva." The results of his experiments, published in
1884, showed that if half the thyroid, or even half of one lobe
were retained, the animal escaped death. In this case transitory
phenomena of functional insufficiency were often apparent.
The rapid course and violence of the phenomena of tetany as
22 PHYSIOLOGY CHAP.
observed in the most robust dogs, after Colzi had excised both
thyroids with a perfect surgical technique, led us to suspect that
the whole pathological syndrome depended on an auto -intoxication.
To prove this hypothesis we suggested that Colzi should perform
direct reciprocal transfusion of blood between two dogs, one that
had been operated on and was in the most acute period of tetany,
the other perfectly normal. On joining a carotid artery of the
first dog with a jugular vein of the second by glass cannulae
united with rubber tubes, the vascular systems of the two animals
completely exchanged their blood content, so that after a few
moments the blood of each animal was perfectly mixed with that of
the other. Previous experiment had shown that reciprocal trans-
fusion can be borne for over half an hour, a period more than
sufficient for the total mass of the blood of the two animals to be
physiologically affected by the thyroids of the healthy dog, since
we know that half a thyroid suffices for each dog.
The effects obtained by this experiment, as frequently repeated
by Colzi, were what we had predicted. On suspending the trans-
fusion after 20-30 minutes, the dethyroidised dog no longer showed
symptoms of tetany, and seemed to have reverted to the condition
it was in on the day of the operation. This more or less complete
disappearance of pathological symptoms lasted only for two or
three days, after which they set in with their former violence, and
rapidly induced the death of the animal. The dog with intact
thyroids appeared depressed for some hours after the transfusion,
but soon recovered and became perfectly normal.
These results, as obtained for the first time in our laboratory,
were the initial demonstration of the theory that the thyroid
apparatus has an antitoxic function, a theory essentially different
from that of Schiff, and confirmed, as we shall see, by subsequent
researches. At the Session of the Medico-Physical Academy of
Florence, July 13, 1884, we formulated our fundamental theory as
follows, on the strength of Colzi's experiments. " The function of
the thyroid secretion is to withdraw from the blood, and probably
to destroy, a product of tissue katabolism that tends to accumulate
slowly, and is capable, when accumulated, of producing a species
of auto -intoxication analogous to the uraemia consequent on
bilateral extirpation of the kidneys. The presence of the entire
thyroid is not indispensable for this cleansing function, a half or
quarter of it will suffice."
Although Schiff s experiments had established the fundamental
fact that the pathological symptoms consequent on thyroid-
ectomy were essentially phenomena of glandular deficiency, other
authorities referred these phenomena to the operative lesions,
more particularly of the nerves, — adopting the hypothesis of
Eeverdin. H. Munk, in repeated publications (1887-88, 1897),
and contrary to the observations of other experimenters, maintained
i INTERNAL PROTECTIVE SECRETIONS 23
that dogs often bear up well against the effects of bilateral thyroid-
ectomy, provided there are no lesions of the sensory nerves of the
region, and that the total occlusion of the thyroid vessels was
equally without effect.
The direct confutation of Munk's opinion is given more
particularly by the experiments on dogs of Fuhr (1886), Fano
(1893), and Vassale (1893), which prove that lesions of the nerves
and vessels of the neck, translocation of the thyroids and the
grafting of them subcutaneously, have no sequelae, and that
suppression or complete ablation of the gland are alone capable of
producing the symptoms described by Schiff. Vassale proposed
an experimentum crucis : if the thyroid lobe be excised from a dog
on one side, and the sympathetic nerves divided on the other, this
double operation is not followed by phenomena of cachexia and
tetania thyreopriva.
At a later time E. Cyon (1897-98) formulated a new hypo-
thesis to explain the effects of thyroidectomy. His theory at first
seemed highly suggestive, but it proved fallacious in face of
many facts that have received experimental confirmation. Cyon
attempted to fuse the old theory of Schreger-Liebermeister with
that which attributes a secretory antitoxic function to the thyroid,
directed, i.e., to the removal of some toxic matter from the body
as a whole, and more particularly from the nervous system.
His hypothesis may be summed up as follows : —
(a) The function of the thyroid gland is to form and pour
into the blood a special substance designed to stimulate or keep
up the functional tonus of the nerve centres which regulate the
beats of the heart. This substance is thyro-iodine (discovered, as
we shall see, by Bauniann among the active substances of the
thyroid, infra, p. 30).
(&) In proportion as thyro-iodine is formed by the activity of
the glandular epithelia, the iodine salts circulating in the blood
which have a paralysing action upon the regulatory apparatus of
the beats of the heart (Barbera and Cyon), are withdrawn from the
circulation and remain innocuous, forming organic combinations.
(e) By means of the depressor nerves and cardiac branches of
the recurrent nerve, the heart exerts a direct control over the
thyroid function, determining the formation of the amount of
thyro-iodine that is necessary for its normal activity.
(d) The thyroid, which lies at the entrance of the carotids into
the cranium, is a protection against an excessive flow of blood to
the brain, since it can carry off a great quantity of blood through
its vessels in a very short time. It therefore acts as a secondary
circulation of low resistance.
(e) This regulatory function of the cerebral circulation attri-
buted to the thyroid is also controlled by the heart, since the
depressors are able to determine the active dilatation of the
24 PHYSIOLOGY CHAP.
thyroid arteries, by reducing the quantity of blood that flows to
the brain.
The fallacy of Cyon's theory becomes obvious when we
remember, on the one hand, that the effects of thyroidectomy are
totally avoided in dogs by preserving the two upper halves of the
two thyroid lobes (Sanquirico and Canalis), or even one upper half
of one lobe (Colzi) ; on the other, the double clinical syndrome of
cachexia and tetany exhibited in man after extirpation of the
thyroid, with the various associations and successions of the two
categories of phenomena consequent on thyroidectomy in dogs.
The most direct and convincing refutation of Cyon's hypothesis,
however, lies in other important experimental facts which must
now be examined.
VIII. We have seen that the first generic proof of the theory
which regards the sequelae of thyroidectomy as phenomena of
auto-intoxication from accumulation in the blood of the katabolic
products of the various tissues, resulted from the direct reciprocal
transfusion between two dogs, one dethyroidised and the other
normal, as performed under our directions by Colzi in our
laboratory. The conclusion we arrived at of the protective
antitoxic function of the thyroid gland, was too important for the
work not to be taken up and repeated by many investigators and
with various methods.
Eogowitsch (1886-88) was the first to verify these results.
Next in order, with more variation in detail, came the experiments
of Fano and Zander (1889), and of Lusena (1889).
Starting from these fundamental notions, Gley (1895) con-
ceived the happy idea of comparing the degree of toxicity of blood
serum from a healthy dog with that of a dog suffering from tetany
and cachexia thyreopriva, by injecting these sera into frogs,
guinea-pigs, and rabbits. He came to the conclusion that the
toxicity of the serum of dethyroidised dogs, as compared with that
of the normal dog, is exhibited in these animals by different and
more acute symptoms, i.e., by severe convulsions.
The toxicity of the urine in dethyroidised animals also increases
relatively to that of the urine of healthy animals. This fact,
which was at first denied by Alonzo (1890), was clearly established
by Gley (1894), and was subsequently confirmed by Laulanie and
by Maison (1894).
Eeasoning from this fact, which shows that the toxic substances
that accumulate in the blood after thyroidectomy are eliminated
by the organism through the renal excretory system, Dutto and
Lo Monaco (1895) were led to suspect that the intoxication
consequent on thyroidectomy occurred by a process analogous to
that which produces uraemia, more particularly as the symptom-
atology of the latter is no less varied, and presents not a few points
of resemblance with cachexia thyreopriva. This suggestion was
i INTEENAL PEOTECTIVE SECEETIONS 25
tested in our laboratory by the so-called washing of the blood in
dethyroidised dogs, i.e. the repeated injection into the veins of an
isotonic solution of sodium chloride in quantities large enough to
increase the urinary secretion and accelerate the elimination of
all the toxic products accumulated in the blood. Our results
were approximately identical with those obtained by Fano ; after
each injection the morbid symptoms were alleviated or entirely
disappeared for some time.
This temporary cessation of all the symptoms is strictly
associated with the increased diuresis, and thus with the normal
functions of the kidneys. When the latter are affected and do
not expel the excess of injected fluid fast enough, the symptoms of
cachexia are not suspended.
Another important fact appears from the researches of Dutto
and Lo Monaco. These authors found on methodical analysis of
the urine that elimination of nitrogenous waste products diminishes
in dethyroidised dogs, so that they accumulate in the body : the
washing of the blood abolishes the symptoms of cachexia thyreo-
priva because it determines the elimination by way of the kidneys
of these nitrogenous products, which had been retained and
accumulated in the body.
These experimental results as a whole reinforce the hypothesis
formulated by ourselves, to the effect that the toxic substances
which determine tetany and cachexia thyreopriva are katabolic or
waste products from the tissues, i.e., they have the same origin,
and, in part at least, consist of the same urinary materials. It
appears from certain experiments of Vassale and Eossi (1893) that
these toxic substances are largely derived from the muscles, which
represent the tissue that predominates considerably over any other
in the body. These authors studied the degree of toxicity of the
juice prepared from the muscles of normal dogs, compared with
that of the muscles of dogs killed when suffering from tetany and
cachexia thyreopriva. The muscular extract of healthy dogs
yielded negative results : the muscular extract of dogs in tetany,
on the contrary, when injected into the veins of dogs that were
normal or recently deprived of the thyroid, induced the gravest
symptoms, — anorexia, vomiting, fibrillar contractions, and event-
ually convulsions.
If (as appears highly probable from what we have been stating)
the phenomena of tetany and cachexia thyreopriva really depend
on auto-intoxication ; if the toxic substances by which this is
determined are the waste products from the various tissues, notably
from the muscles which form the predominating tissue ; if these
toxic katabolites are normally eliminated by the renal system as
fast as they are formed, then the protective, antitoxic action of the
thyroid secretion may validly be conceived as the direct or indirect
effect of a physiological excitation of the renal epithelia. The
26 PHYSIOLOGY CHAP.
phenomena of thyroid insufficiency will thus consist mainly in the
effects of the progressive accumulation in the blood and tissues of
these products, owing to the altered or retarded secretory function
of the epithelium.
That the kidneys do not function normally in dethyroidised
animals may be argued from the alburninuria that accompanies
tetania thyreopriva, as also from the lesions which are invariably
found in the kidneys of dethyroidised animals, ranging from a
simple albuminoid degeneration of the epithelia of the canaliculi
to severe parenchymatous nephritis (Alonzo, Hofmeister, etc.).
Blum (1901) found nephritic alterations of greater or less
gravity in dogs that had survived thyroidectomy for at least eight
days. He, too, attributed the origin of these to auto-intoxication,
which according to him is of an enterogeneous nature, due, i.e., to
the suppression of the antitoxic activity of the thyroid, which
normally has the task of destroying the enterotoxins.
Bensen (1902), again, who particularly devoted himself to the
histology of the lesions of various organs in the rabbit incident
on thyroidectomy, arrived at a conclusion that coincides with the
above. He admitted that, "after thyroidectomy, owing to the
suppression of the thyroid gland, a poison is produced or retained
in the body, which determines a characteristic degeneration of the
cell protoplasm, especially in the kidneys, liver, and myocardium,
leading eventually to the destruction of the cells. The products
of protoplasmic degeneration appear in the form of colloidal
spherules or cylinders in the renal canaliculi. When the morbid
state is protracted an interstitial nephritis is readily set up, leading
to the formation of scars, similar to those which Blum describes
in dogs."
The theory of the intimate functional relations between the
thyro-parathyroid apparatus and the kidneys, however, finds its
fullest experimental confirmation in the studies of Coronedi (1907)
and his pupils. In the first place, this author observed that the
alterations of the kidney (consisting in inflammatory and de-
generative processes) in animals exhibiting symptoms of a defective
thyro-parathyroid system is a constant fact, certain to appear,
and, at least within certain limits, proportional to the intensity
and gravity of the pathological symptoms. It is worth noting that
the lesions may be present even when the syndrome of symptoms
has scarcely been initiated.
While the amount of katabolites increases after excision of the
thyroid and parathyroids, and the elaboration of these products is
never fully accomplished, the functional capacity of the kidneys
diminishes pari passu. Hence a true intoxication of retention
ensues, which, if not identical with, is at any rate highly similar
to, uraemia.
Coronedi believes that among its other functions the internal
i INTEENAL PEOTECTIVE SECEETIONS 27
secretion of the thyro-parathyroid apparatus serves mainly as
a physiological diuretic (stimulating the nutrition and specific
activity of the renal epithelium). He arrives at this conclusion
from studying the action of the gland-extract upon the kidney,
and noticed that the salutary effects of thyro-parathyroid organo-
therapy and of the halogenated fats which are its equivalent, are
entirely wanting or become less, with experimental alteration of
the kidney.
IX. Schiffs ingenious idea of transplanting and grafting the
thyroid to avert the fatal effects of thyroidectomy opened up a
wide field of research, which is interesting both from the
physiological and from the therapeutic point of view. After he
had demonstrated that preventive intraperitoneal grafts of fresh
thyroid are capable of prolonging the life of dogs that were sub-
sequently deprived of their thyroids, it was natural to conclude
that the same treatment might obviate the serious consequences
of total thyroidectomy in man, and be a cure for spontaneous
myxoedema.
Bircher (1889) was the first to graft a piece of human thyroid
into the abdomen of a dethyroidised patient, who exhibited
symptoms of cachexia. He obtained a temporary improvement
which was repeated after a few months on renewing the graft.
Horsley (1890) attempted the cure of spontaneous myxoedema
by grafting under the skin or in the peritoneum, the thyroids of
sheep or monkeys (which are histologically very like those of man),
after proving that thyroidectomy in these animals produces a
syndrome which closely resembles human myxoedema. The results
were so encouraging that this method of cure was repeated in a
short time by many others, among them Lannelongue, Kocher,
Bettencourt and Serrano, Meiien, etc.
The most interesting results were, however, obtained by
Eiselsberg (1892), who repeated Schiffs experiments on cats, trans-
planting an excised lobe not to the peritoneum, but to the thick-
ness of the abdominal wall, and then a month later — when the
graft might be supposed to have taken — excising the other lobe.
Of the many cats thus operated on, four long survived and
exhibited no morbid symptoms. Three months after grafting,
Eiselsberg exposed the transplanted gland, and found that it was
attached by vascular adhesions ; he then excised it again, and
found normal glandular structure under the microscope. Two
days after this second operation the animals developed acute
tetany, and soon died. It is thus possible, even if exceptional,
for the transplanted thyroid to become rooted in other than
its normal surroundings. This is an experimentum crucis, by
which the too - ingenious theory which Cyon founded entirely
upon the peculiar nervous and vascular relations of the thyroid
is invalidated.
28 PHYSIOLOGY CHAP.
These experiments have recently been confirmed by Christian!
(1901) on a large number of animals.
He gives certain important details in regard to the method of
performing the thyroid grafb so that it shall take well.
No arbitrary quantity of thyroid can be grafted, but only such
an amount as is required by the body in each individual case. If,
e.g., a whole thyroid is grafted on a completely dethyroidised rat, it
may become attached as a whole, but if a whole thyroid, or several
thyroids, are grafted] on a partially dethyroidised rat, a part only
takes root, corresponding, to a certain degree, with the deficit.
This shows that the action of the thyroid is, generally speaking,
more useful to the body in proportion as the maximal intensity of
its function is contained within physiological limits.
Graves' or Basedow's disease, which is characterised by a
well-known complex of symptoms (tachycardia, oesophthalmia,
increase of general katabolic processes, etc.) is now attributed by
the majority of clinicians to exaggerated activity of the thyroid,
whatever the conditions which initiated it. The same syndrome
is also exhibited when thyroid preparations are administered to
persons whose thyroid is normal, as, e.g., with the therapeutic object
of reducing obesity.
However efficacious in this direction, the cure is so dangerous
owing to its tendency to produce the symptoms of Graves' disease,
that it has now been generally abandoned (Striimpell).
Eiselsberg, having failed with other clinicians in the radical
cure of spontaneous or operative myxoedema by thyroid grafting,
owing to the difficulty of regeneration, put in practice Schiffs
suggestion by preparing a thyroid extract, and injecting it beneath
the skin of dethyroidised animals. His results, however, were not
encouraging, either from the position of the injection, or from the
amount of juice injected. Vassale was more fortunate. At the
end of 1890, independent of Eiselsberg, seeing the therapeutic
efficacy of certain drugs injected directly into the veins (Baccelli),
he injected large quantities of thyroid juice into dethyroidised
dogs, and obtained a beneficial, though transitory, action from such
injections. These results were amply confirmed by Gley (1891),
and applied very successfully by Murray (1893), both in a case
of spontaneous myxoedema and in a monkey deprived of its
thyroids.
A year after Murray's first cure of myxoedema Howitz,
Mackenzie, and Fox substituted the administration of thyroid by
the mouth for venous injections. This method is very simple, and
within the grasp of all ; and it gives surprising therapeutic
results in cases of myxoedema which have gone on for years, and
proved refractory to all kinds of treatment. This shows that the
active principles of the thyroid juices are not decomposed by the
action of the digestive secretions.
29
The salutary effect, both of injection of thyroid juice and of
thyroid ingestion by the mouth, is probably owing to the fact that
it facilitates the elimination of the toxic products accumulated in
the blood. In this connection the following observation of Vassale
is interesting : " After the injection of thyroid juice," he wrote in
1892, "the animal as a rule drinks water, sometimes in very large
quantities ; it subsequently excretes an excessive amount of urine,
after which it returns to its normal condition, and remains well
for at least twenty-four hours. It seems as though the animal
drinks much water in order, with the large amount of urine it
then evacuates, to wash the body free of a toxin that had previously
accumulated in the blood and tissues." This gives weight to our
hypothesis that the thyroid secretion normally has the function of
directly or indirectly exciting renal secretion.
The work of Godard and Slosse, carried out under Heger's
direction, also supports this point of view. According to these
experiments, the thyroid juice has a lymphagogic action, analogous
to that exhibited by the lymphagogues of Heidenhain's second
category (Vol. I. p. 523 et seq.\ which indirectly promote diuresis
by transporting water and the products of katabolism into the
lymphatic sinuses and vessels and the blood.
From the physiological point of view these results show that
the protective action of the thyroid depends on the specific
character of the chemical substances which it contains, and which
normally pass into the blood by continual internal secretion.
Many workers have therefore devoted themselves to research in
this direction by chemical analysis of the thyroid juice. Their
results are interesting, though inadequate for the solution of this
difficult problem.
Notkin (1895) prepared a special substance from calf's thyroid
which he termed thyreo - protein ; this on injection into a dog
recently deprived of its thyroid induced phenomena of tetany
that subsequently ceased, to reappear at each fresh injection. He
concluded that it was this substance (normally retained by the
thyroid and rendered innocuous) which causes the auto-intoxica-
tion consequent on thyroidectomy. In addition to thyreo-protein .
Notkin isolated another indefinite substance from thyroid extract
which he termed thyreo-gummin ; this acts upon the former and
transforms it into an innocuous substance, necessary to the nutrition
of the body. He was in fact able to neutralise the noxious effects
of thyreo-protein by simultaneous injection of thyreo-gummin.
These very suggestive results have not, so far as we know, been
repeated or confirmed by other workers.
Frankel simultaneously affirmed that the active principle of
the colloid substance, or secretion, which the thyroid pours into
the lymph and blood system, is a mucin, which he obtained from
the watery extract of boiled and filtered thyroid. He called it
30 PHYSIOLOGY CHAP.
thyroid-antitoxin, and maintained that it was capable of inhibiting
the appearance of cachexia when injected into dogs deprived of
the thyroid.
These experiments of Notkin and Frankel were abandoned as
soon as the work of Baumann (1895-96) appeared. He proclaimed
the discovery of iodine in the thyroid, and raised hopes that the
active principle of the thyroid had been found in an organic
compound of iodine, to which the name of thyro-iodine was given.
Baumann, with Koss and with Goldmann, Hofineister, Hildebrand
and Irsai, maintained that the injection of thyro-iodine into the
veins was able to compensate for the functions of the thyroid
when that organ had been excised. The experiments of Gottlieb
(1896), Wormser (1897), and Pugliese (1898) contradicted this
vicarious action of thyro-iodine. According to Wormser, thyro-
iodine is "neither capable of impeding the onset of an attack
of tetany nor of arresting an attack that is already running
its course."
On the other hand, by injection of the gland, as a whole,
whether administered by the mouth or injected into the veins in
the form of an extract, in sufficient quantity, it is possible to
check the paroxysms of tetany, and to keep the dethyroidised
animals ah' ve for a long time, as was first demonstrated by Vassale.
Other facts tell against Baumann's theory. According to his
own researches, the thyroid of dogs after a flesh meal contains
either no iodine or the merest traces of it. Iodine is rarely found
in the pig's thyroid ; hardly any, or merely a trace, in the thyroid
of sheep and horse (Topfer). The human thyroid does not contain
it constantly (Baumann). The subsequent researches of Neu-
meister and Malthes (1897) showed that iodine is frequently
absent in the thyroid of adults and infants, and that while that
of the ram and pig contains 50'9 mgrms. of iodine per gramme of
dry gland, that of the dog, horse, and calf contains either none or
merely traces of it. Thyro-iodine cannot therefore be the active
principle required, although it is probable that the iodine, intro-
duced in minute doses with vegetable aliments, is retained and
fixed in organic form by the thyroid gland. It has been observed
that the iodine of the thyroid increases after the medicinal use of
iodides and iodoform.
On the other hand, the experiments of Coronedi and Marchetti
on the biological importance of halogens to the function of the
thyro - parathyroid apparatus have thrown new light on the
subject. They actually succeeded in rendering animals (dogs and
rabbits) perfectly immune against cachexia and tetany, and
were able to cure them easily, when already attacked, by the
administration of iodine or bromine in an alimentary form
(halogenated fats), which can easily be stored in the adipose
tissue of these animals, since, in comparison with normal animals,
i INTERNAL PROTECTIVE SECRETIONS 31
they have a decided tendency to retain such halogens in the
body. When the organic supply of halogen comes to an end, as
may occur after months or even years, the characteristic symptoms
of thyro-parathyroid deficiency reappear.
Bunge (1898), on the simple ground of analogy, propounded
the hypothesis that the protective antitoxic substance secreted
by the thyroid consists in an unstable protein compound, belonging
to the enzyme group, with the property of producing large effects
by infinitesimal doses. When poured into the blood along with
the colloidal substances, this enzyme would influence the metabo-
lism of the body and accelerate the elimination by the renal outlets
of the katabolic products as fast as these are formed. But as
yet no experiments are to hand in direct evidence of this
hypothesis.
X. In order to explain the fact that some animals (rabbits
constantly, and dogs in certain rare cases) can bear the complete
ablation of the thyroid without injury, Schiff (supra] proposed
the hypothesis that the body contains another organ capable of
supplementing the functions of the thyroid. This hypothesis led
to a number of ineffective researches, with the object of determining
which this vicarious organ could be.
Fano (1893) showed that the removal of one suprarenal
capsule, of the salivary glands, the ovaries, and a large portion of
the pancreas, produced no modification in the sequelae of subsequent
total thyroidectomy.
That no functional relation exists between the thyroid and
the spleen was plainly shown by the experiments of Tizzoni and
Fileti (1883-84), of Sanquirico and Canalis (1884), of Ughetti and
Mattel (1885), and others. In 1893 Zanda revived the subject,
and stated that thyroidectomy was not fatal in dogs, if performed
about a mouth after splenectomy. Had these results been con-
firmed, they would have been of great importance, justifying the
hypothesis put forward by Zanda, that the spleen pours toxic
products into the blood, which the thyroid renders innocuous.
Unfortunately, the later experiments of Fano, Vassale, and Di
Brazza proved that dogs and cats, deprived of their spleen, were
liable more than a month afterwards to the effects of thyroid-
ectomy, like normal animals.
The principal argument against the existence of any functional
relation between spleen and thyroid rests on the recent histological
work of Massenti and Coronedi on the first of these organs in the
dethyroidised dog. The spleen undergoes a process of sclerosis
and atrophy, which is the more advanced in proportion as the
survival power of the animal to thyro-parathyroidectomy is
greater.
Nor was the work of Marie and Mobius, of Cadeac and Guinard
(1894), who sought to establish a functional relation between the
32 PHYSIOLOGY CHAP.
thyroid and the thymus, more successful. Gley (1894) demon-
strated the fallacy of this theory.
Attempts to demonstrate a functional relation between the
thyroid and the glandular portion of the cerebral hypophysis or
pituitary gland succeeded better. These results will be referred
to below, in their proper connection.
It is to Gley (1892) that we must ascribe the merit of having
pointed out the importance of the parathyroid glands, previously
discovered by Sandstroni. Along with the thyroids, he excised
the two little glands of Sandstroni in rabbits, which died, under
these circumstances, with symptoms of tetany, even when the
removal of the parathyroids was effected a month later than that
of the thyroids. But when the parathyroids alone were excised
in rabbits, no pathological symptoms appeared. He concluded
that the parathyroids acquire great importance only after the
extirpation of the thyroids — probably because they have the
function of vicariously replacing them. In confirmation of his
hypothesis, Gley observed that the parathyroids become hyper-
trophic a month after the excision of the thyroids, and exhibit
modifications by which their structure approximates to that of
the thyroids, as if they were embryonic thyroids intended to
supplement any functional insufficiency of the adult gland.
Subsequently, in collaboration with Phisalix (1893), he per-
formed the same experiment on dogs, and came to the conclusion
that these animals also survived the complete extirpation of the
thyroids, when precautions were taken to spare the parathyroids
and leave them in situ; while symptoms of tetany inevitably
supervened, when the latter were also extirpated. Ablation of
the parathyroids alone did not, according to Gley, produce morbid
sequelae. This confirmed his theory of the supplementary function
of the parathyroids.
His conclusions were, however, contested by Moussu (1893),
Hofmeister (1894), and particularly by Vassale and Generali
(1896). These authors disputed Gley's observations as to the
structural modifications of the parathyroids after removal of
the thyroids. But as Rouxeau (1896) confirmed the fact of the
conspicuous increase of the parathyroids after thyroidectomy, and
the innocuous effects of simple parathyroidectomy, many people
adopted Gley's view of the functional interchanges between the
thyroid and parathyroid glands.
Gley's hypothesis was first shaken by the accurate work of
Vassale and Generali (1896), which showed that a specific
functional importance distinct from, and even greater than that
of the thyroids must be granted to the parathyroid glands. These
authors excised the parathyroids only on numerous dogs and cats,
and found that they succumbed rapidly, the cats usually in 5, the
dogs in 3 to 4 days after the operation, i.e. the more rapidly in
i INTERNAL PROTECTIVE SECRETIONS 33
proportion as the thyro-para thyroid excision was more complete.
Sometimes the animals succumbed after incomplete ablation of
the parathyroid glands, i.e. when one parathyroid only was left
in situ, as usually occurs in the case of dogs that have more than
four parathyroids. As a rule, however, the animals that survive
partial thyroidectomy exhibit slight and transitory pathological
symptoms. These are analogous to the effects of thyro-parathy-
roidectomy — acute phenomena of " tetania thyreopriva," which is
speedily fatal, or slight and transient, according as the para-
thyroidectomy was complete or partial. When partial para-
thyroidectomy is associated with total thyroidectomy, the chronic
phenomena of cachexia thyreopriva set in, with or without slight
convulsions.
In view of their significance, the experiments of Vassale and
Generali were at once repeated and confirmed in France by
Moussu (1897). Of four dogs on which he performed total
thyroidectomy, three died of tetany on the 2nd and 7th day,
and the fourth survived because (as shown at the post mortem) it
had a fifth supernumerary parathyroid.
Edmunds and Welsh (1898) independently repeated and con-
firmed the results of Vassale in England.
The same work was continued in Italy by Capobianco and
Mazziotti (1899), and more extensively by Lusena (1899). The
latter, in a fine series of comparative experiments on dogs,
shows —
(a) That the (chief) characteristic symptom of thyro-para-
thyroidectomy is coma, the period from the operation till death
being on an average 1 0 days ;
(&) That the characteristic symptom of parathyroidectomy is
tetany, the interval between the operation and death being usually
3 days;
(c) That the excision of the thyroid, including the two internal
parathyroids (which, as we shall see, are included with them) is
not fatal if perfect nutrition is maintained in the two external
parathyroids which are left in situ.
Lusena, in order to confirm the fact that the presence of
the thyroids aggravates the pathological syndrome of total
parathyroidectomy, conceived the idea of excising the thyroids
in dogs already deprived of their parathyroids, which were on
the point of dying from tetany, and saw that the convulsive
phenomena were gradually attenuated, and a state of comparative
amelioration introduced, so that the fatal issue was postponed.
The effects of parathyroidectomy can also be attenuated by
the so-called substitutive therapeutics, i.e. by hypodermic, or better
intravenous, injections of aqueous extract of the parathyroids
alone. These experiments were performed almost simultaneously
by Moussu and by Lusena (1898). Moussu showed that such
VOL. II D
34 PHYSIOLOGY CHAP.
injections, besides suspending the phenomena of tetany, effected
a sensible prolongation of the life of the animal. Lusena added
the further fact that injections of pure thyroid juice exerted no
beneficial influence on the syndrome of parathyroidectomy or
thyro-parathyroidectoruy, and that the injection of the juice
prepared from the thyroids of dogs that had tetany from para-
thyroidectomy, aggravated the symptoms of thyro-parathyroid-
ectomy. This last result rests on a single experiment only, and
deserves to be confirmed by further research.
Lastly, Lusena has established by the method of reciprocal
transfusion, or that of the partial substitution of the blood by an
isotonic solution of sodium chloride, that the phenomena of tetany
in parathyroidectomy can be suspended or attenuated like those
of thyro-parathyroidectomy. In the first as in the second case,
accordingly, there must be toxic substances in the blood of the
animals that have been operated on.
All these interesting data as to the functional importance of
the parathyroids throw new light upon many obscure points, and
subtract not a Little from the value of the earlier conclusions as
to the physiology of the thyro-parathyroid system.
We can now see why rabbits and other animals frequently
survive complete extirpation of the thyroids, and why even dogs,
on which the greatest number of experiments have been carried
out with positive results, may also survive. This is evidently
due to the fact that the external parathyroids are constantly in
rabbits, and occasionally in dogs, distinct from the thyroid lobes,
and are therefore left in situ when those lobes are excised.
So, too, we can explain why, after excision of goitre, the patient
may only exhibit symptoms of a slowly progressing cachexia
thyreopriva or operative myxoedeuia, while in other less frequent
cases acute phenomena of tetany supervene. Previous to the
investigation of the parathyroids, these two essentially distinct
pathological forms were regarded as different steps of one identical
process, due to the abolition of the function of a single gland,
the thyroid. Cachexia thyreopriva is now held to be the effect of
functional deficiency of the thyroid gland alone, and tetany the
effect of inhibited function of the parathyroids. In excision of
goitre by the subcapsular method, the surgeon in the majority of
cases -leaves the inferior parathyroids, which are distinct from
the thyroid lobes ; but in certain cases the inferior parathyroids
are included in the ablation of the thyroid, being joined to the
body of it. In the first case cachexia ensues, in the second tetany.
Sometimes there may be transitory or intermittent tetany, in
consequence of functional insufficiency of the parathyroids. This
occurs, according to Vassale, when a single inferior parathyroid
is left in situ during the operation. In order to avert this
pathological consequence, it is necessary for the operator to spare
i INTERNAL PROTECTIVE SECRETIONS 35
the lowest portion of the thyroid body, as well as the inferior
parathyroids.
Opinions differ at present as to the functional relation between
the thyroid and the parathyroids. Gley (1898) was inclined to
admit the existence of such an association between them, and
to think that the parathyroids prepared a substance which is
subsequently taken up and poured into the circulation by the
thyroids. According to Moussu, Vassale, and Generali, on the
other hand, the two glandular functions are independent and differ
specifically from one another. The thyroids have an essentially
trophic function, i.e. they secrete substances indispensable to
good general nutrition, particularly to the nervous and skeletal
systems; the parathyroids, on the contrary, have an antitoxic
function, i.e. they neutralise or facilitate the elimination by the
kidneys of the toxic substances formed during metabolism.
How, then, are we to explain the fact suspected by Vassale and
established by Lusena, to the effect that after simple parathyroid-
ectomy the convulsive nervous symptoms are more grave, and
lead more rapidly to a fatal issue, while after thyro-para-
thyroidectomy they are less serious and run a more protracted
course ? In order to account for this difference Lusena assumes
that in dogs deprived of the parathyroids only, the quantity of
toxic substances circulating in the blood is greater than that
circulating after complete thyro-parathyroidectomy. He believes
that the thyroids normally have the property of subtracting from
the blood the materia peccans of unknown character, to return it
transformed and innocuous ; and he holds this antitoxic function
of the thyroids to be dependent on the normal function of the
parathyroids, so that when the latter are removed a larger amount
of poison circulates in the blood.
This bold hypothesis does not — it seems to us — explain
the fact that the subsequent excision of the thyroids con-
spicuously attenuates the symptoms of tetany consequent on
parathyroidectomy. If, after removal of the parathyroids, the
thyroids are no longer capable of abstracting and transforming
the materia peccans in the blood, it is difficult to see why their
extirpation should diminish the symptoms of auto-intoxication.
Vassale's theory is simpler, and suggests a better interpretation.
He holds the specific function of the thyroid gland to be that of
pouring into the circulation a secretion that excites and promotes
general metabolism. The myxoedema consequent on functional
deficiency of the thyroid exhibits a complex of symptoms which
clearly indicate a reduction or perversion of the metabolic
exchanges, and the therapeutic action of thyroid juice or of
ingestion of thyroid in spontaneous or post-operative myxoedema
is characterised by phenomena of quickened metabolism. The
parathyroids, on the contrary, have a specific antitoxic function.
D i
36 PHYSIOLOGY CHAP.
This may be because they throw into the circulation a secretion
that accelerates the renal elimination of the products of tissue
consumption ; and these in all probability constitute the materia
peccans. The tetany consequent on parathyroidectomy is a neces-
sary consequence of the accumulation of katabolites owing to the
defective function of the parathyroids, and the therapeutic action
of parathyroid juice is the proof that the parathyroids contain
protective antitoxic substances.
On this assumption it is easy to understand why parathyroid-
ectomy alone determines an acute auto-intoxication, and thyro-
parathyroidectomy a less acute auto-intoxication, which runs a
slower course. In the first case, where general metabolism is
active, owing to the presence of the thyroid, the amount of
toxic matters accumulating in the blood is larger ; in the second
it is, on the contrary, smaller, because metabolism is reduced
owing to absence of the thyroid. This is the reason why the
de-parathyroidised animal is attacked by morbid symptoms, when
subjected at a later period to thyroidectomy.
In support of his views Vassale adduces the following experi-
mental data : —
(a) The phenomena, of " tetania parathyreopriva " are more
serious in young than in very old animals.
(6) The said phenomena are more acute and more rapidly fatal
to the animal, if it eats much, especially meat, after the operation.
(c) Fasting reduces the pathological syndrome consequent on
thyro-parathyroidectomy.
(d) In animals deprived of the parathyroids alone, when
metabolism is normal, cicatrisation of the wound in the neck
occurs regularly by first intention ; in animals deprived of the
whole thyroid body it is on the contrary difficult — in spite of
every antiseptic precaution — to obtain healing of the wound
per primam, owing to the sluggish metabolism.
In conclusion, we must add that, according to the latest
researches of Alquier and Theuveny (1907), and of Vassale's pupil
Massaglia (1908), the renal lesions which are, as we have seen,
inevitable on the extirpation of the entire thyro- parathyroid
system, are in reality due solely to the suppression of the para-
thyroids, their secretion no longer being able to neutralise the
toxic products of metabolism, which therefore injure the renal
system, producing albuminuria and tetanic convulsions.
The pathological anatomy of man confirms the experimental
data from other animals, i.e. it teaches us that the tetany of
thyroid excision, the so-called " tetania thyreopriva" is only a
"tetania parathyreopriva." We owe to Erdheim some careful notes
on serial sections of the organs of the neck in three persons who
died from tetany after excision of the thyroid. In two of these
the parathyroids were entirely wanting, in the third, one only
i INTEKNAL PEOTECTIVE SECKETIONS 37
remained, and that was necrosed. These three cases, therefore,
verified what experiments on animals had indicated. To-day
every surgeon agrees with Vassale's conclusions that in thyroid
excisions it is essential, in order to avoid a fatal tetany, to spare
at least one or possibly two of the parathyroids (the two inferior
parathyroids).
Another form of human disease which is also characterised by
violent convulsions, and which is known as eclampsia gravidica,
has recently been attributed by Vassale and his pupils to
functional insufficiency of the parathyroid apparatus. To support
this theory Vassale invokes the following facts : —
In the first place, he observed and described a case of tetany of
lactation and pregnancy in a partially parathyroidectomised bitch,
in which after some five years of apparently normal life after the
operation, suckling and pregnancy provoked violent convulsive
epileptiform fits, which were cured by specific organo-tberapy.
Other authors had already observed independently that the
female of dogs or cats, in which the thyroid apparatus had been
partially extirpated, are attacked during pregnancy and parturition
with acute convulsions (Verstraeten and Vanderlingen, Lange).
According to Vassale, the convulsions in this experiment also, in
which thyroidectoniy involved parathyroidectomy in the dog or
cat, were due to parathyroid insufficiency.
Another no less valid argument in favour of the parathyroid
theory of the pathogenesis of eclampsia gravidica is seen, according
to Vassale, in the beneficial effects observed in certain cases of
spontaneous eclampsia gravidica with specific organo- therapy, on
administration of parathyroidine.
More recently, Vassale has found further evidence for
the parathyroid theory of eclampsia in the following observa-
tions : —
(a) Pathological, the post mortem showing alterations or con-
genital loss of one or two parathyroids in the bodies of eclamptics
(Pepere, Zanfrognini).
(6) Clinical, since it has been found possible to prevent and
even overcome the spasm by the administration of parathyro-
iodine (Zanfrognini, Stradiviri, Brun, Vicarelli, Kaiser).
(c) Experiments on cats, on female rats, and gravid bitches,
which show that in latent parathyroid insufficiency convulsive
phenomena regularly break out in the final stage of pregnancy
(experimental eclampsia of Zanfrognini, Erdheim, Thaler, and
Adler, Vassale, Massaglia and Sparapani).
Lastly, it should be added that certain workers (Pineles,
Chvostek and Yanase) express the opinion, on clinical and ana-
tomical grounds, that all the varied pathological forms of tetany
in man are in pathogenic relation with insufficiency of the
parathyroid glands.
D2
38
PHYSIOLOGY
CHAP.
XI. The Pituitary Body (hypophysis cerebri) consists of two
distinct parts or lobes (Fig. 7). The posterior lobe, which is
greyish-yellow, is an outgrowth from the third ventricle of the
brain ; it has no glandular structure and is probably a rudimentary
organ of no importance — in vertebrates at any rate. The anterior
lobe, on the contrary, which is reddish in colour, and is much
more highly developed than the posterior lobe, has quite a distinct
function, and is derived from the primitive pharynx. At a certain
point in embryonic development it appears as a pouch, which is
empty at first, and subsequently fills by the development of
Fir,. 7. — Hypophysis or pituitary body. A, lateral aspect, showing relations with sella turcica.
B, posterior aspect. C, sagittal section, a, anterior lobe of hypophysis (pituitary body
proper) ; b, posterior or nervous lobe ; c, pineal peduncle ; d, optic chiasnia ; e, infundibulum ;
/, optic foramen ; g, quadrilateral plate of sphenoid ; h, sulcus occipitalis.
epithelial cells disposed in groups or columns, which recall the
structure of the parathyroids. Two kinds of cells can be distin-
guished, the chief cells and the chromaphile (Fig. 8).
The latter have a special affinity for stains, and react like
" colloid " substances ; they are probably more developed than the
chief cells, and serve for the secretion of a hyaline substance,
in analogy with the epithelia of the thyro- parathyroid system
(Lothringer). The secretion passes into the lymphatic spaces of
the surrounding connective tissue, and also in part to the blood-
vessels, in which it may for short distances replace the blood
entirely (Pisenti and Viola).
Experiment on the functions of the pituitary body has led to
INTERNAL PEOTECTIVE SECEETIONS
39
divergent, often indeed contradictory, results. Hypophysectomy,
initiated with little success by Horsley, Dastre, Gley, Marinesco,
was pursued with a better technique by some of the Italian
workers.
Vassale and Sacchi (1892-94), in a considerable number of
experiments on cats and dogs, obtained the survival of a few
individuals, in which the hypophysis had been totally or partly
destroyed by cauterising with chromic acid, a method that is
certainly not free from objection.
The first symptoms observed in these animals is that of great
depression and complete apathy, making them indifferent alike to
caresses or ill-treatment.
Motor disturbances, at
first slight and afterwards
more intense, set in. These
consist of fibrillary move-
ments, muscular contrac-
tions, rigidity of posterior
limbs, curvature of back,
unsteady gait,lastly clonic-
tonic spasms of varying
intensity, in the course of
which the animal suc-
cumbs without the slight-
est trace of infective or
other complications being
I- j ,•• Fio. 8.— Section of pituitary body of horse. Stained with
dlSCOVered at tne pOSt Weigert's method. (Lothringer.) The lighter, principal
IYlOrt"PlTl AVitb thpSP ce"s can be distinguished from the darker, chromaphile
symptoms are associated
anorexia, tachypnea, polyuria, growing density of highly alkaline
urine (without either albuminuria or glycosuria), hypothermia,
rapid and progressive emaciation, coma not infrequently preceding
death, which occurs in 2-11 days after the operation.
Gatta (1896) and Kreidl and Biedl (1897) repeated these
experiments, and obtained results which agreed approximately
with those of Vassale and Sacchi.
The syndrome obtained by Caselli (1900) in his many experi-
ments on hypophysectomy in both dogs and cats was somewhat
different : depression of mental powers, motor disturbances,
curvature of back, spastic gait without convulsions, progressive
cachexia, rapid loss of weight, coma, death.
This syndrome has undeniable resemblances with that which
appears after excision of the thyro-parathyroid organs, justifying
the surmise of Eogowitsch (1888) that the pituitary and the
thyroid glands are homologous, and are therefore able to function
vicariously. In order to discover why rabbits always support
thyroidectomy without injury, he made a microscopic examination
40 PHYSIOLOGY CHAP.
of the various organs of these animals in search of possible
modifications. The glandular part of the hypophysis proved to
be considerably larger in volume, with bigger follicles, and more
colloidal substance in the interfollicular spaces. This led him to
conclude that in rabbits the hypophysis might supplement thyroid
deficiency.
The experiments of Rogowitsch were repeated and confirmed
by Stieda (1890), Hofrneister (1882), Gley (1892), and others.
Tizzoni and Centanni (1890) observed the same facts in three
dogs that long survived total thyroidectomy as Rogowitsch had
noted on rabbits, and came to a similar conclusion. Schonemann
(1892) adduced the results of clinical observation in support of
the same thesis, and demonstrated a hypertrophy of the pituitary
body in cases of goitre, when a great part of the parenchyma of
the thyroid gland does not function. These observations, although
contradicted by Schwarz, have recently been confirmed by Corute.
This theory of a close relation and functional substitution
between the thyroid and the hypophysis was shaken by the work
of Vassale and Sacchi, and of Caselli, while the later observations
of Gaglio on amphibia (1900), and of Lo Monaco and Van Ryn-
berk in our laboratory (1901) on dogs, proved that the syndromes
brought forward to support it are not the necessary and direct
consequences of loss of the pituitary body.
Moreover, Luzzatto, working in Coronedi's laboratory on the
hypophyses of animals that long survived the total ablation of
the thyro-parathyroid apparatus, never succeeded in finding any
morphological indication of hypertrophy of the pituitary body
from exaggerated function.
The same negative results were obtained by Friedemann and
Maass in Germany, and more recently by Dalla Vedova (1903) in
the Institute of Surgery in Rome. Thus, whatever may be the
function of the pituitary body, we now know that it is not of
sufficient importance for its complete ablation necessarily to
bring about the death of the animal, provided the technique
is satisfactory.
Nor did Cyon's experiments (1898-1902) lead to more
positive results. Starting from his work on the thyroid he
assumed that the hypophysis co-operated with this organ in
maintaining equilibrium of endocranial pressure, founding his
theory upon the alterations of pressure consequent on injections
of pituitary extract obtained by various methods. It may be
remarked that the results of various experimenters as to the
role of the supposed active principles of the pituitary gland
differ widely. According to Szymonowicz (1898) pituitary
extract diminishes blood pressure and accelerates the pulse:
Schafer and Swale Vincent (1899) say that it raises blood pressure ;
Mairet and Bosch (1896), that 'it excites the nervous system;
i INTEENAL PEOTECTIVE SECEETIONS 41
Osborne and Vincent, on the contrary, that it has a depressing
action ; Howell (1897), that it retards and reinforces the pulse ;
according to Cyon, lastly, it contains two active substances, the
one retarding, and the other accelerating, the pulse.
Cyon thought he had demonstrated that the hypophysis
regulates endocranial pressure, slowing and strengthening the
pulse, and reducing blood pressure, by the fact that its direct
stimulation by gentle mechanical compression and weak electrical
currents, produced these effects. It is difficult to determine
exactly how much of this interpretation can be accepted. The
situation of the pituitary body justifies the assumption that its
excitatory impulses are transmitted by the lobule of the infundi-
bulum to the cardiac centres of the vagus. If this be so, it plays
no part in the production of the phenomena described.
Gaglio, moreover, found that in frogs operated on by hypo-
physectomy, the bulbar centres of the vagus are as excitable to
increased blood pressure, not only days and weeks, but also a few
hours, after the operation, as in normal frogs. This does not agree
with Cyon's observations on rabbits.
Nor has clinical observation thrown more light on the functions
of the hypophysis. Since Marie and Marinesco (1891) suggested
that acromegaly was the expression of a systematic dystrophy,
consequent on functional disturbance of the pituitary body, many
new facts have militated against their theory. Collina (1898)
diligently collected all cases of this disease in which there had
been a post mortem. He found that in a large majority the tumour
was represented by adenomata and sarcomata. On the other hand,
as was observed by Striimpell (1897), hypophysal tumour is not
invariably present in acromegaly, while such a tumour often
occurs without acromegaly. As regards organo-therapy, Mendel
and Marinesco (1895) noticed improvement with pituitary ex-
tract ; Schultze, on the contrary (1897), denied that it had any
beneficial action.
The function of the hypophysis is therefore wholly un-
determined, and it may be stated in conclusion that of the
various far-fetched and improbable theories, that proposed by
Eogowitsch as above appears least hazardous, although it has
not been demonstrated.
Among the more recently acquired experimental data the
following should be noted.
Gruerrini (1904) found, by a series of microscopic researches
on various animals, that the pituitary body, in every alteration
of metabolism due to endogenous or exogenous intoxication,
exhibits phenomena of functional irritation analogous to those
shown in other glandular organs; if protracted, these may lead
to hypertrophy and hyperplasia of the parenchyma of the gland.
Fichera (1905) in a first series of experiments (macroscopic
42
PHYSIOLOGY
CHAP.
and microscopic) on fowls, buffaloes, oxen, rabbits and guinea-
pigs, concluded that there is an intimate relation between the
hypophysis and the sexual glands (testicles, ovary), which, as we
shall see elsewhere, are also the seat of an important internal
secretion.
He found in castrated animals that removal of the testicles or
ovaries led rapidly to hypertrophy and hyperplasia of the pituitary
body, which showed histological modifications indicative of func-
tional hypertrophy. If the castrated animals are treated by
organo-therapy with the sexual glands, the irritative phenomena
of the parenchyma of the hypophysis are
reduced and eventually disappear.
In a second series of experiments, Fichera
(1905) destroyed the hypophysis in fowls by
a new method of operating. He found in a
number of experiments, confirmed by micro-
scopic examination, that this organ was not
indispensable to life. Animals that survived
its total destruction merely exhibited an arrest
of development, particularly as regards the
skeleton.
Gemelli has recently obtained almost
identical results.
Cerletti (1906 - 8), studying in young
guinea-pigs, rabbits, dogs, and lambs the effect
on somatic growth of continuous injection of
Fm. 9.— Bight kidney and „ ° . J
suprarenal body of a full- extract ot lamb s hypophysis, showed that
view" (AntnUSThoTn^o°n.) this substance particularly affects the de-
velopment of the skeletal system, although
in an opposite sense to what might be expected
from the preceding experiments. He con-
cluded from his observations that persistent
dosage with pituitary extract retards the growth of the body in
general, as shown most deleteriously for the skeletal system, where
the activity of the connecting cartilages (delay in lengthening of
long bones) is conspicuously diminished, while the activity of the
periosteal ostogenic function (increased development of depth of
epiphyses and diaphyses) is, on the contrary, augmented. Control
animals treated with extracts of other organs (thyroid, muscle) did
not exhibit similar changes.
The results of these new experiments indicate that the hypo-
physis is a gland of internal secretion, serving in some way to
excite or regulate the metabolism of the body and the development
of its various organs, particularly of the skeletal system. While
too indefinite to represent an exact theory of the function of the
hypophysis, this view is, on the other hand, supported by clinical
observations on acromegaly and gigantism, which are often, if not
s, suprarenal capsule ', v',
vein issuing from it ; ?%
foetal kidney ; v, renal
artery and vein emerging
from hilium ; u, ureter.
INTERNAL PEOTECTIVE SECRETIONS
43
always, accompanied by hypertrophy and hyperplasia of the
pituitary body.
XII. The Suprarenal Capsules or Adrenals are two epithelial
flattened bodies of a yellowish- brown colour, situated above the
FIG. 10. — A, Human suprarenal body ; vertical section. (Eberth). 1, cortical substance ; 2,
medullary substance ; a, capsule ; b, zona glomerulosa ; c, zona fasciculate ; d, zona reticularis,
e, groups of medullary cells ; /, section of a large vein. B, cortex of dog's suprarenal ; vertical
section. (Bohin and v. Davidoft'.) a, fibrous covering; b, zona glomerulosa; c, zona fasci-
culata ; d, zona reticularis.
kidneys, each weighing about four grammes. They reach their
maximal development during intra- uterine life. Their size
is considerable in proportion to that of the kidneys in the
foetus at term (Fig. 9). This fact, discovered by Meckel, was
confirmed for man by A. Ecker and H. Frey. It does not, how-
ever, signify (as Bischoff maintained) that the functions of the
suprarenals are in relation with embryonic life, since they would
44
PHYSIOLOGY
CHAP.
in that case atrophy after birth, whereas their growth continues,
though very slowly, till the adult age (Brown-Sequard).
In section, the fibrous sheath is succeeded by a broad cortical
layer, hard, striated in appearance, and dark yellow, which forms
the principal mass of the gland, and an inner, medullary part,
soft and brownish in colour: the .older anatomists took this to. be
a 'dense secretion collected in a cavity, from which they incorrectly
designated the whole organ a capsule (Fig. 10, A).
From the fibrous sheath, which often contains plain-muscle
cells (Fusari), fine septa or trabeculae are given off into the
organ, and serve as a framework which supports the columns
of polyhedral epithelium
cells.
Three zones can be dis-
tinguished in the cortex,
better in some other animals
than in man, which are differ-
entiated by the arrangement
of the epithelium cells : these
are known as the zona
glomerulosa, the zona fasci-
culata, and the zona reticu-
laris (Fig. 10, B).
The medulla is separated
from the cortex by a sheet of
loose connective tissue. It
is composed of a network,
the meshes of which enclose
Fio. 11.— Medullary substance of suprarenal body of cell - Columns which differ
ox, stained haematoxylin. (Vassale.) a, resting '
cells; 6, cells in active function, filled with ironi those OI the COrteX in
chromaffine substance which is discharged directly u • i i i
into the wood capillaries. being larger, less granular,
more irregular in form, and
vacuolated, and they stain a brown colour with solutions of
chromic acid and its salj;s, while the cortical cells give hardly
any such reaction. Owing to this specific property the medullary
cells have been termed chromaffine or chromaphile (Kohn), a term
now frequently used to distinguish the medullary from the
cortical substance (Fig. 11).
The difference between the two parts of the adrenal glands
is not confined to this histological peculiarity. According to
recent work in embryology and comparative anatomy, the
medullary and the cortical substance represent two perfectly
distinct and independent organs, which in the majority of verte-
brates fuse together during foetal development, and apparently
form only one single organ. In the Elasrnobranchs, on the
contrary, the two organs remain separate during the whole of the
animal's life. Balfour (1877) showed that these fishes have no
45
"suprarenal capsules" analogous to those described in mammals, but
possess two sets of perfectly distinct organs : —
(a) The inter-renal body, an unpaired glandular structure,
homologous with the cortical substance of the adrenal gland in
mammals.
(6) The suprarenal bodies, arranged in pairs, in close relation
to the ganglia of the sympathetic chain, homologous with the
medullary or chromaffine substance of the adrenal glands.
These results have been confirmed and amplified by recent
workers, among them being
Diamare and Giacomini in
Italy.
The work of embryologists
(of Kohn, in particular) on
mammals, including man, has
fully confirmed the double nature
of the suprarenals. In fact,
while the cortical substance is
mesoblastic in origin (Wolffian
body), the medullary substance
is derived from the phaeo-
chromoblast, one of the two
groups of embryonic cells into
which the primary sympathetic
(ectodermic) cells become differ-
entiated. All such chrornaffine
or chromaphile cells derived
from sympathetic ganglion rudi-
ments were classified by Kohn
as paraganglia. At a later
period of development the bulk
of the chromaffine or (as Poll
termed it) phaeOChrome tissue FlG. 12._Schematic reconstruction of paragang-
lion in new-born rabbit. (A. Kohn.) A, aorta ;
C, suprarenal body ; P, abdominal paragang-
lion, which, with its prolongations, .joins the
medullary substance of the suprarenal cap-
sules ; p, p, p, small nodular paraganglia.
enters into relation with the
epithelial substance of the
cortex, in which it is englobed,
and thus forms the medulla of
the gland or "suprarenal paraganglion " (Fig. 12). The whole
of the chromaffine tissue derived from the mother-cells of the
sympathetic ganglia is not, however, enclosed in the capsule :
some of the smaller masses remain in various regions more
or less adherent to the sympathetic ganglia or the blood-vessels.
These nodules of chromaffine substance constitute the carotid
and sacral glands, Zuckerkandl's parasympatlietic body or abdo-
minal aortic paraganglion, etc., which have long been observed
without definite knowledge as to their origin and significance
(Fig. 13). They are now shown by recent work in embryology,
46
PHYSIOLOGY
CHAP.
histology, and experimental physiology, to be organs entirely
similar to the medullary substance of the suprarenal bodies.
Chromamne or " paragangliar " tissue is thus closely related to
the nerve cells of the sympathetic system, being in fact differ-
entiated from the same embryonic group of cells. In adult
animals it is still intimately connected with the sympathetic
Fiii. 13.— (Left.) Parasympathetic bodies of Zuckerkandl (human). Prom an anatomical pre-
paration of Sperino and Balli. A, aorta; V, vena cava; ar, left renal artery; vr, left renal
vein ; op, parasympathetic bodies, or paraganglia ; a' v', artery and vein of right paraganglion ;
a"v", artery and vein of left paraganglion; mi, inferior mesenteric artery; v.sp, spermatic
or ovarian vein ; pla, aortic plexus of sympathetic.
Pio. 14.— (Right.) Paraganglion of adult cat. (A. Kohn.) A, aorta ; B, vena cava ; C, suprarenal
capsule ; D, caeliac ganglion ; S, sympathetic ; P, abdominal aortic, filiform paraganglion ;
p, punctiform paraganglia.
system, many ganglion cells being mixed with the cells of
the medullary substance of the suprarenal bodies, while nodules
of chromamne tissue adhere to the sympathetic chain in various
regions (Fig. 14). Chromaffine tissue has accordingly been defined
as " an epithelial tissue of neural origin " (Diamare).
Functionally, too, we shall find an intimate relation between
the sympathetic system and the product of the internal secretion
of chromamne tissue.
The arteries that supply the suprarenals penetrate the cap-
i INTEENAL PEOTECTIVE SECEETIONS 47
sular sheath at various points, after subdividing into small
branches. The veins in the medullary substance form a plexus,
and usually converge into one large vein for each organ, which
leaves by the hiluni. That on the right opens directly into the
inferior cava ; that on the left, after a longer course, into the left
renal vein.
According to Pfaundler, the internal vessels of the suprarenals
have no proper tunica externa and media, only a thin wall consist-
ing solely of intinia.
The lymphatics course through the trabeculae of the cortical
substance, and are connected with the lacunae or fissures lying
between the trabeculae and the columns of cells, and between the
cells themselves (Klein). In the medullary substance the lymph-
atics, which are provided with valves, form a plexus that interlaces
with the venous plexus, and surrounds the central vein.
Both suprarenal bodies and paraganglia contain an enormous
number of nerves deriving from the splar and the renal plexuses
(Fig. 15). They are mainly medullated fibres of different sizes,
interspersed before entering the capsule with a number of small
ganglia. They ramify between the cells of the cortex, and are
most abundant in the zona glomerulosa. In the medulla there
are many ganglion cells united in groups, and nerve fibres,
which are distributed to the vessels and also perhaps to the
gland-cells.
In rare cases one or both suprarenal bodies are absent. More
frequently there are accessory adrenals, which vary in size from a
pin's head to that of a pea. The smallest have no medullary
substance (Eolleston). These accessory capsules are usually found
in the neighbourhood of the capsule itself ; but they are sometimes
partially embedded in the kidney or liver, the broad ligament of
the uterus, and along the spermatic vessels.
In 1789 Cassan observed that the suprarenal capsules are
larger in the negro than in Europeans, which led him to suspect
that these organs are in some relation with the formation of
cutaneous pigment. Meckel subsequently confirmed Cassan's
observations, but held the greater development of the capsules
in negroes to be in relation with that of the genital organs.
These anatomical observations of Cassan and Meckel are in line
with the work of Addison, published in 1855, which promoted
experimental investigation of the suprarenal bodies, and may be
said to have initiated the physiological study of these glandular
organs.
XIII. Addison was the first to describe a form of disease
which is nearly always fatal, and is characterised by a state of
progressive anaemia, pronounced weakness of cardiac beat,
great irritability of stomach, and general atony of nervous and
muscular system, with abnormal brown or bronzed patches on
48
PHYSIOLOGY
CHAP.
the skin. From this last very apparent symptom, he named the
new form of disease "bronzed skin." Addison believed it to
depend on deficiency or functional insufficiency of the suprarenals,
of which he recognised the great physiological importance. He
further held that there was a relation between the absence or
diminished function of the suprarenals, and the amount of pig-
ment deposited in the skin. By diligent research into the
FIG. 15. — Transverse section of abdominal aortic paraganglion of adult cat. (Vassale.) u, sym-
pathetic ganglion ; 6, 6, b, nerves ; c, paragangliar or chromaftine tissue.
pathological anatomy of almost every one who had died of
" bronzed skin," he discovered profound alterations in the capsules
of various kinds, more particularly of a tuberculous nature.
Starting from Addison's researches, Brown-Sequard (1856)
performed a series of experiments on animals, and came to the
same conclusion as the English pathologist, viz. : that the supra-
renal capsules were organs indispensable to life.
On destroying the capsules, Brown-Sequard found that they
i INTERNAL PROTECTIVE SECRETIONS 49
are peculiarly sensitive in rabbits, which give cries of pain when
one of these bodies is crushed in the forceps. Those of dogs, cats,
and particularly guinea-pigs are less sensitive.
When one capsule only was excised or destroyed by crushing,
Brown-Sequard invariably noted the death of the animal (rabbits,
guinea-pigs, dogs, cats) in less than three days. But he sub-
sequently found that destruction of the right capsule alone was
not fatal. Immediately after the operation the animals rotated
upon their own axis, now in one, now in the other direction, and
the pupils of the side operated on were found to be more con-
tracted. These are inconstant phenomena of stimulation, due
probably to the method of crushing adopted by Brown-Sequard,
in which the many ganglion cells contained in the organ are
violently excited.
The suppression of both capsules invariably kills the animal,
rabbits in 9-10 hours, dogs and cats after 49 hours at most. As a
rule young animals survive longer than adults.
In consequence of the suppression of the capsules, the animals
fall into a state of profound lassitude, which differs from that con-
sequent on any other severe and painful operation by it's sudden
onset after 10-15 minutes. The weakness increases, and 15-20
minutes before death assumes the form of regular paralysis, attack-
ing first the hind - limbs, then the fore - limbs, and lastly the
respiratory muscles. Sensibility persists to the last hour, and may
even be exaggerated. Convulsions are frequent in the hours
previous to death. The respiratory and cardiac movements are
usually accelerated at first, and then become progressively weaker.
Appetite disappears : digestion is suspended : urinary secretion, on
the contrary, continues normal. The temperature falls consider-
ably (from 4°-5° C. in winter).
Brown-Sequard, by special experiments, demonstrated that the
excision of both capsules usually involves the death of the animal
more rapidly than ablation of the kidneys. Hence he regarded
them as organs indispensable to life, the death which follows
their removal being due to the lapsed function of the suprarenals.
These data at once aroused opposition. Gratiolet and
Philippeaux (1856-57-58) in France, Berruti and Perosino (1857-63)
in Italy, denied the inevitable death of the animals operated on,
and referred it either to operative traumatism, or to peritonitis
or other secondary effects. Brown - Sequard did not reply
exhaustively to all the criticisms, and the question of the func-
tional importance of the suprarenals remained for a long time a
matter of controversy. The subject has been revived of late, with
strictly aseptic methods, by a number of workers who have con-
firmed, developed, and extended to other glandular organs the
conclusions of Brown Sequard, to whom therefore belongs the
honour of having founded the doctrine of internal secretion.
VOL. II E
50 PHYSIOLOGY CHAP.
Cases of survival of the animal after the excision of both
capsules are rare, and must be explained either by incomplete
extirpation or by the existence of accessory suprarenals
(Szymonowicz). The most important points in the rich modern
literature of the physiology of the capsules may be briefly
summarised.
The methodical research undertaken by Abelous and Langlois
(1891-92) on the frog showed that—
(a) Complete destruction of the capsule by the method of
cauterisation inevitably causes death (after 12-13 days in winter,
after 48 hours in summer) with symptoms of progressive paralysis,
which commences in the lower limbs (24-30 hours after the
operation) and subsequently becomes general and produces death.
(6) General paralysis follows more rapidly if the frog is
frequently excited after the operation, so as to provoke muscular
movements.
(c) Destruction of one capsule alone produces no morbid effects
in the frog : complete destruction of one capsule and of the greater
part of the other determines death in most cases, but after a
longer time. Death is then invariably preceded by convulsions
and dyspnoea.
(d) On grafting the capsules of a normal frog into the dorsal
sac of the decapsulated frog, the survival period of the latter is
doubled. On dissection, the graft is found not to have taken, the
capsules being reduced in volume and decolorised. Injection of a
watery suprarenal extract results in a less marked prolongation
of life.
(e) Intravenous or subcutaneous injection of the blood of a
moribund, decapsulated frog into a frog that has been recently
operated on, causes rapid paralysis and death. The same injec-
tion into a normal frog produces only slight and transitory
disturbances.
(/) If immediately after destroying the capsules in a frog the
sciatic is exposed, and a thread tied round the leg at a lower
point, by Bernard's method, while the blood from a moribund
decapsulated frog is injected under the skin, then at a certain
stage of intoxication (3 hours after injection) the most powerful
induction shocks have no effect on the sciatic of the free limb,
while a weak current easily borne by the tongue produces
energetic contractions from the sciatic of the ligatured limb.
Direct application to the muscles of either leg produces contrac-
tions, which are, however, stronger in the tied than in the free
limb.
From these facts Abelous and Langlois concluded that death
from removal of the capsules is due to the accumulation in the
blood of one or more toxic curarising substances, i.e. such as act
like curare on the end-plates of the motor spinal nerves, and in a
i INTERNAL PROTECTIVE SECRETIONS 51
less degree upon the muscles. Albanese, independently of the
French investigators, confirmed their results, and brought out still
more clearly the influence of muscular fatigue upon duration of
life in decapsulated frogs. He held the toxic substances of
unknown nature which determined the fatal effects to be produced
during work by the muscles and nervous system.
Abelous and Langlois performed a second series of experiments
en the guinea-pig, in which the capsules are highly developed in
relation to the total weight. Each capsule on an average weighs
12 cgrms. in guinea-pigs of 500 grms., while in rabbits of 2 kilos,
they only reach 10-15 cgrms., and 1 grm. in dogs. On the other
hand, accessory capsules are very rare in guinea-pigs, while they
frequently occur in rabbits and dogs.
The effects of destroying one capsule only, of partial cauterisa-
tion, and of total destruction of both capsules in the guinea-pig,
tally with the experiments on frogs, and confirm the theory which
Brown-Sequard formulated in 1856, i.e. that the suprarenal capsules
are organs for elaborating substances destined to modify or destroy
the toxins of curarising action which accumulate in the body after
the destruction of the adrenals.
Much work on rats, rabbits, cats, and dogs was contributed by
other observers. The divergence in their conclusions is evidently
due to the variations in operative procedure. Schiff (1863),
Tizzoni (1884), Russo-Giliberti and Di Mattei (1886), Alezais and
Arnaud (1891), Berdach and Pal (1894), Boinet (1895), sustained
that the ablation of both capsules in rats, rabbits, and dogs was
compatible with survival, but we may now assume that they only
partially destroyed these organs, or chanced on animals with
accessory suprarenals.
The results which the brothers Marino-Zuco (1892) obtained
on rabbits agree perfectly with those of Abelous and Langlois on
guinea-pigs. Removal of both capsules was fatal after three to
five days, with paralytic phenomena ; removal of one capsule only
was compatible with survival, and no detrimental changes
occurred in the rabbits that were partially decapsulated on both
sides. But some time after partial capsular ablation, rabbits that
were not albinos frequently exhibited an abnormal distribution of
pigment in the skin or the oral or nasal rnucosa, viz. formation of
bronzed or grey patches in places where they had not occurred
previous to the operation (Nothnagel, Tizzoni, Marino-Zuco).
This phenomenon recalls the abnormal pigmentation of the skin in
Addison's disease.
In conclusion, the long series of experiments carried out in
Tigerstedt's laboratory, by his pupils Hultgren and Andersson
(1899), generally speaking, confirm the preceding researches ; with
the addition of some new and interesting details : —
(a) The excision of both capsules seems always to be fatal in
52 PHYSIOLOGY CHAP.
dogs or cats, after sixty-eight hours on an average : but if the
excision be effected in two or three sittings, life is prolonged by
about double the number of hours. Castrated cats survive the
longest.
(&) Excision of both capsules is fatal to rabbits after five to
six days : but if a certain period intervenes between the two
operations, the animal may live for months without any patho-
logical disturbance.
(c) Partial unilateral or bilateral excisions are compatible
with survival. More or less transitory or persistent symptoms of
functional insufficiency appear, particularly emaciation.
(d) In the final twenty-four to forty-eight hours of survival
of decapsulated animals there is a characteristic lowering of
temperature.
(e) During this hypothermia of collapse, injection of suprarenal
extract raises the temperature again, and improves the state of the
animal. By such injections life may be prolonged for some
twenty-four hours.
(/) Suprarenal extract injected into the veins or beneath the
skin of normal rabbits in a given variable dose, produces death by
oedema and pulmonary haemorrhage.
XIV. Till the opening of the present century the suprarenal
bodies (on the strength of the data above discussed) were
universally regarded as glands endowed with a single, specific,
protective function.
But when further research in comparative anatomy and
embryology brought to light the important fact that the cortical
and medullary parts of the organ are composed of elements
dissimilar in nature and in origin, it became clear that the supra-
renals serve a double physiological function.
In Italy Vassale was the first to take up this position. He
established the special importance of the medullary substance by
a number of experiments (in collaboration with Zanfrognini
1902-3) on the removal of the suprarenal capsules in the cat and
rabbit. With complete ablation of the medullary substance, the
greater part of the cortical substance being left intact, the
animals die with the same acute symptoms as ensue on excision of
the entire suprarenals. If the ablation of the medullary substance
is partial, and small fragments of it are left, the animals die from
serious functional insufficiency after 3-4 weeks, with symptoms of
a special cachexia (anorexia, psychical depression, asthenia, fall of
temperature, marked emaciation).
Independently of Vassale, H. and A. Christiani (1902) excised
the suprarenal glands in rats, with the following results. With
bilateral excision death is rapid and invariable, whether the
operation be performed in one or in two sittings, even if there be
a year's interval between the two operations. Unilateral ablation
i INTERNAL PROTECTIVE SECRETIONS 53
produces no ill -effects. If one capsule is wholly, the other
partially, excised, it is sometimes found that a minute vestige of
the organ suffices to keep the animal alive, while in other cases
death supervenes; although a comparatively large portion of the
organ may remain. Histological examination shows that in the
first case medullary substance has been left, in the second it has
perished. The specific function must, therefore, lie in the
medullary substance.
Another experimental proof of the great importance of the
medullary substance appears from the results of grafting the
suprarenal bodies. Animals subjected to bilateral ablation of both
capsules die, even if other suprarenals are grafted in their bodies,
and become attached. Now, while the cortical substance is
capable of regenerating and becoming rooted in the region into
which the organ is transplanted, the medullary substance does not
survive and degenerates completely (Poll, H. and A. Christiani).
According to Vassale the chromaffine tissue is fundamentally
altered, and loses its capacity of increasing in size by hyperplasia
of its own cells, when, owing to the partial ablation of tissue, the
remainder is forced into functional hyperactivity. The phenomena
of compensatory hypertrophia with cellular hyperplasia, observed
by Stilling (1889), and Wiesel (1899), in the surviving capsule,
or the accessory suprarenal bodies, after the extirpation of one or
both suprarenal capsules, involve only the cortical and not the
medullary cells. Landau (1898) again found in his experiments
on transplantation of the capsule and unilateral capsulectomy that
the taking of the graft in the first case, and the hypertrophy in the
second, are always limited to the cortical substance, and never
involve the medullary.
From these experiments the theory of the heterogeneous
nature and double function of the cortical and medullary substance,
and of the preponderating importance of the latter, seems well-
established. Certain objections, however, may be raised, and have
to be met before the question can be regarded as settled. Kohn
(1903), makes the following criticisms :—
The rare cases in which the bilateral ablation of the suprarenal
bodies was not followed by death, were explained by invoking the
vicarious action of accessory suprarenals remaining uninjured in
the body of the animal (Stilling, 1887). These accessory organs,
however, shew no trace of chromaffine tissue. On the other hand,
some mammals, e.g. cat and rabbit, in which extirpation of the
suprarenal bodies is followed by death, possess in addition to these
organs, conspicuous masses of chromaffine tissue, e.g. on the ventral
surface of the abdominal aorta. Why, he asks, are these masses
not capable of saving the animal from death, since a minute vestige
of medullary substance is able to do so? The results which
Abelous and Langlois obtained from amphibia agree still less with
54 PHYSIOLOGY CHAP.
the modern view, because in these animals the quantity of extra-
capsular chromaffine tissue is comparatively large as compared with
the intra-capsular bulk of the same tissue.
On the other hand, the experimental results of Pettit (1896)
and Swale Vincent (1897), on Teleosteans, give support to the
modern theory. They found that eels for months survived the
ablation of the suprarenal bodies, which in these animals consist
of cortical tissue only. The chromaffine tissue, which, according
to Giacomini (1902), lies near the cardinal veins, escaped the
operation.
In conclusion, Kohn recommends that more attention should
be paid in future to the amount and condition of the whole of the
chromaffine tissue, in the individual animals operated on.
Vassale (1905) subsequently attempted by special experiments
to decide how great an importance attaches to the extra-capsular
chromaffine tissue.
In kittens, extirpation of one capsule and of the abdominal
aortic paraganglion may determine death with the same symptoms
that are observed after bilateral ablation of the suprarenal bodies,
or the bilateral removal of their medullary substance. In the
adult cat the same operation does not induce rapid death ; the
animal succumbs after about ten weeks, during which period,
although it eats with great voracity, it becomes more and more
emaciated, and perishes of marasmus. Dogs will tolerate the
removal in a first operation of one capsule and the abdominal
aortic paraganglion, and in a second, of the half of the remaining
capsule ; on the other hand, they cannot bear this triple removal
if performed in a single sitting — the animal then succumbs in
twenty-four hours.
Vassale showed that in the dog and cat the extra-capsular
chromaffine tissue varied in amount from animal to animal in the
same species, and suggested on the strength of his experiments
that the survival of some animals after decapsulation in successive
sittings was to be explained by the quantity of chromaffine tissue
or of extra-capsular paraganglia. The satisfactory state of animals
operated on in one or many sittings by maximal capsulectomy, or
partial excision, leaving the animals enough capsule to keep them
alive, is due, according to Vassale, to adaptation only. Since the
remaining chromaffine tissue (he says) is incapable of hyperplasia,
although it does exhibit some functional hyperactivity, true
compensation of the lost functions cannot take place.
Admitting that the cause of death in animals exposed to
bilateral capsulectomy is to be ascribed exclusively to the sup-
pression of the medullary or paragangliar substance of the supra-
renal bodies, we still have to define the specific functions of the
cortical substance. Vassale and Zanfrognini have proposed the
hypothesis that the destruction of this part may be associated with
i INTERNAL PROTECTIVE SECRETIONS 55
remote morbid phenomena, similar to or identical with the trophic
and cutaneous disturbances of Addison's disease. The latter are
seldom obtained experimentally because, with total capsulectomy,
the animals nearly always die with acute predominating symptoms
of severe asthenia and paralysis, due to the suppression of the
medullary substances.
XV. We cannot doubt, therefore, that the protective function
of the double glandular organ formed by the suprarenal capsule
must consist in arresting the action of one or more poisons
normally formed in the body, and that the phenomena of deficiency
or functional insufficiency of these organs are phenomena of
intoxication. Numerous experiments have been made to determine
the nature of these toxins, their mode of acting on the body, and
the process by which the capsule renders them inactive.
As early as 1857 Vulpian noticed that the liquid extracted
from the suprarenal capsules contains a special chrotnogenic sub-
stance, which, when exposed to the air, turns gradually carmine-
red. The reaction is produced instantaneously with oxidising
agents such as chlorine-, bromine-, and iodine- water. Krukenburg,
in 1885, returned to the study of this chromogen, and reported
that it gave certain reactions characteristic of pyrocatechin.
Brunner (1892) confirmed the results of Krukenburg, and Moore
(1895-97) succeeded in determining the chemical properties of the
chromogen of the capsule more exactly.
Manasse (1893-94) found a substance in the blood of the
suprarenal veins which turned brown when treated with potassium
bichromate, and which is certainly secreted by the suprarenal
capsules.
It is highly probable that these facts are in relation with the
theory of Addison's disease, which attributes to the capsule
(probably to the cortical part) the function of regulating cutaneous
pigmentation. In what exactly this relation consists is unknown.
According to Nabarro (1895) the suprarenal capsules contain
globulins and nucleo-proteins that precipitate with magnesium
sulphate, and coagulate at 56°, 65°, and 75° C. An albumin is
also present which coagulates at 71° C.
It has been shown by F. Marino-Zuco (1888) and F. Marino-
Zuco and Dutto (1890-91) that the suprarenal capsules normally
contain a considerable amount of neurine, and that individuals
attacked by Addison's disease eliminate appreciable quantities of
this base by the urine. Gruarnieri and Marino-Zuco (1888), on
injecting solutions of glycerophosphate of neurine in minute doses
into rabbits, obtained phenomena of intoxication similar to those
observed after excision of the capsules. Albanese (1892) found
great sensibility of frogs, as well as of decapsulated rabbits, to
neurine. Half a milligramme injected under the skin of the back
(an insignificant dose to a normal frog) produces serious symptoms
56 PHYSIOLOGY CHAP.
of intoxication, and even death, if the frog is not very large. The
dose of 1 mgrm. is always fatal to the decapsulated frog, while it
takes 4 mgrms. to kill one that is normal. On the other hand, the
brothers Marino-Zuco state that either the excision of one capsule
alone, or the injection of non-toxic doses of neurine will after
fourteen to twenty-four days cause slate-grey spots to appear on
the skin, the buccal rnucosa, and the under surface of the tongue.
These experimental data are the basis of the theory sustained
by Marino-Zuco and Albanese, viz. that Addison's disease and the
effects of artificial destruction of the capsule are due to neurine
intoxication, and that the function of the capsules consists in
modifying the neurine produced by the body, so as to render it
innocuous.
In order to explain the process by which the capsules neutralise
the activity of neurine, Carbone (1894) carried out a series of
experiments to determine its effects upon normal and decapsulated
dogs, tested by its elimination in the urine. He found that the
normal dog bears a hypodermic injection of small doses of neurine
without any symptoms ; in the decapsulated dog, on the contrary,
the same dose immediately produces salivation, and after a few
hours, vomiting, diarrhoeal discharges, paralysis of the hind limbs.
This led him to suspect that in the normal dog the neurine was
rapidly destroyed or fixed by the capsule, while in the decapsulated
animal it circulated and was eliminated unchanged in the urine.
In order to verify this surmise, Carbone estimated the neurine
eliminated by the urine, and found that the amount did not vary
perceptibly in the normal dog .and in those which had suffered
ablation of three-fourths of both capsules. In both cases, only a
small part, at most a fourth, of the injected neurine passes into
the urine. The remainder is probably transformed or retained in
the body.
In regard to the theory that the toxins causing the cachexia
of Addison's disease consist in neurine or glycerophosphate of
neurine, Neumeister points out that the neurine and glycero-
phosphoric acid found in the capsules may come from decom-
position of their lecithin or choline, owing to manipulation of the
chemical extracts. On the other hand, Oliver and Schafer (1895)
showed that the effects of injecting phosphate and glycero-
phosphate of neurine are totally different from those produced by
suprarenal extract in toto.
Taken as a whole, these data leave no doubt as to the protective,
antitoxic action of the suprarenal capsules, but it is still uncertain
if this is effected by the removal from the blood of specific toxic
substances, or by the secretion and output into the blood and
lymph of one or more active substances, which are directly or
indirectly antitoxic.
According to a theory brought forward by Cybulski (1895), the
i INTEENAL PEOTECTIVE SECRETIONS 57
entire morbid syndrome exhibited acutely after total destruction
of the capsules, depends on the depression of tone in the vasomotor,
cardiac, and respiratory centres, and also in all probability of the
centres of muscular tone.
The active substances produced by the capsules (which reach
the blood by the suprarenal veins) thus serve to keep up the normal
tone of all these centres.
This view is supported by a series of experiments carried out
partly with the collaboration of Szymonowicz, which may be
summarised as follows : —
(a) After complete extirpation of both capsules (which the dog
only survives for eight to fifteen hours) the arterial pressure falls
to 20 mm. Hg below the normal ; pulse and respiration become
considerably slower. Intravenous injection of aqueous supra-
renal extract raises pressure conspicuously, slows the pulse, and
quickens respiration ; while the injection of other organic extracts
has no effect.
(&) After section of the cervical cord, injection of suprarenal
extract has no effect, showing that the increase of pressure is due
to excitation of the bulbar vasomotor centre. On cutting the vagi,
the slowing of the pulse caused by injection of the extract ceases,
showing it to be due to stimulation of the moderator centres of
the heart.
(c) The active substance is formed not after death, but during
the life of the suprarenal bodies, passing by diffusion into the
epithelial cells of the efferent veins. In fact, if the reduced venous
blood from the capsule is collected and defibrinated, and then
injected into the veins of an animal, the same phenomena are
produced as are seen after injection of suprarenal extract, though
less acutely. The venous blood from any other vein has no effect
in the same doses. These results were confirmed by Salvioli and
Pezzolini (1902).
(d) A long series of experiments shows that the active substance
formed by the suprarenals is not toxic in moderate doses, but
merely raises the tone of the vasomotor, respiratory, and cardiac
centres, as well as the centres for muscular tone.
(e) The transitory nature of the excitation of the above centres
by the active substance manufactured by the capsule, is explained
on the assumption that it is partly eliminated by the kidneys,
partly transformed by oxidation within the tissues. Probably the
increase of arterial pressure, the slowing of the pulse, and the
dyspnoea that accompanies the asphyxia, depend on the accumu-
lation within the body of the active substances formed by the
capsule, which under normal conditions are destroyed as fast as
they form.
The exact physiological action of suprarenal extract on various
tissues has been recently studied by Velich, Biedl, Wiesel, Gottlieb,
58
PHYSIOLOGY
CHAP.
Pick, Langley, Elliott, Gioffredi, Salvioli, Patta, Vassale, Bottazzi,
and many others. Contrary to the opinion of Cybulski, most
authors now admit in explanation of the enormous vaso-constrictor
action of this substance, that it acts peripherally upon the muscular
cells of the vascular coats (directly, or indirectly by means of the
sympathetic nerve endings), as was stated by the first investigators,
Oliver and Schafer. The experiments of Velich and Biedl, who
divided and destroyed the spinal centres, give direct support to
this view, together with those of Gottlieb, who eliminated the
action of the vasomotor centres by profoundly chloralising the
animals ; and still more the fact adduced by the last author, that
Fio. 10.— Effect of suprarenal extract on blood pressure in curarised rabbit. (Verworn.)
1, injection of extract ; 2, section of both vagi.
the vaso-constrictor action also takes effect in the vessels of isolated,
surviving organs (kidney, mammalian heart).
The active principle of the suprarenal capsules does not
produce the same contractile effect on all the plain muscle of the
body as is thus distinctly exerted upon the vascular muscle-cells.
On other involuntary fibres it has an exactly opposite effect,
causing their active expansion or relaxation, and depression of
tone (Lewandowsky, Boruttau, Langley).
Langley (1901) described the effects of suprarenal extract on
various organs with plain muscle, in cats and rabbits. Com-
mencing with the results of minimal doses, and going on to those
of strong doses of the extract, an enormous increase in blood
pressure due to peripheral vaso-constriction first appears (Fig. 16);
then relaxation of the cardiac sphincters, intestines (rabbit) and
bladder, dilatation of the pupil (cat), retraction of the nictitating
membrane (cat), opening of the eyelid (cat). Next follows con-
traction of the uterus, of the vasa deferentia, spermatic vesicles
i INTERNAL PROTECTIVE SECRETIONS 59
(rabbit), salivary and lachrymal secretion, relaxation of the
stomach and gall-bladder, increase of biliary secretion, pupillar
dilatation, paralysis of the internal sphincters, etc. This shows
that suprarenal extract produces sometimes relaxation, sometimes
contraction, in different tracts of plain muscle.
Boruttau, Pal, and afterwards Langley and Bottazzi, showed
that the peristaltic movements of the intestine are inhibited by
suprarenal extract. "When the active principle (known as para-
gangline, Vassale, and adrenaline, Takamine) is applied to an
isolated strip of toad's oesophagus or stomach, Bottazzi (1904)
FIG. 17. — Effect of paragangline on plain muscle fibres of toad's oesophagus. (Bottazzi.) 1, injec-
tion of extract ; 2, its removal by washing. The curves show the very slow contractions of
longitudinal fibres of oesophagus. The cylinder revolves about once in twenty -four hours.
observed a marked depression of tone in the plain muscle of these
organs (Fig. 17).
To explain the dissimilar action of the same active suprarenal
principle on various organs of plain muscle, Langley laid stress on
the important fact that the action of this substance almost invari-
ably provoked the same effects as artificial stimulation of the
sympathetic, which, as we know, induces sometimes relaxation,
sometimes contraction in different organs with plain muscle. His
pupil Elliott (1905) confirmed this fact with more ample demon-
stration by means of adrenaline for all the tissues of the body,
whether sympathetically innervated or not. Without entering
too fully into details, his conclusions are as follows : —
In all vertebrates the reaction of a given group of plain muscles
to adrenaline has the same character as that produced by excita-
tion of the visceral sympathetic nerves (lumbar-thoracic) which
60 PHYSIOLOGY CHAP.
innervate the same muscles. The effect may consist in contraction
or in relaxation. If the plain muscle has no sympathetic innerva-
tion (e.g. involuntary bronchial muscles), it is indifferent to the
action of adrenaline. Neither the ganglion cells and nerve fibres
of the sympathetic, nor the muscular fibre -cells, are directly
attacked by adrenaline. Its action is, on the contrary, localised in
the end-organs, which unite the nerve fibres with the muscle
substance.
These conclusions of Langley and Elliott, based on experi-
mental data, demonstrate clearly that there is a close connection
between the active principle of the suprarenal bodies (which are
more especially provided with chromaffine cells) and the sympathetic
nervous system. This tallies with the conclusions of embryology
and comparative anatomy, according to which, as we have seen,
chromaffine tissue has a common origin with the sympathetic
system.
As regards the physiological action of the active suprarenal
principle, it must be stated in conclusion that various authors (in
addition to its influence on smooth muscular tissues) have ascribed
to it a characteristic action on metabolism. Blum (1901) noticed
that subcutaneous and intravenous injections of this substance
caused elimination of glucose by the urine. This glycosuria,
known also as suprarenal diabetes, was subsequently confirmed
and variously interpreted by other workers (Zlilzer, Crofton, Noel
Paton, Herter and Wakeman, Aronsohn). According to Landau
the substance which on injection produces glycosuria in rabbits
exists in the cortical and not in the medullary substance. A
causal relation exists between the capsule and the diabetes which
is produced by puncture of the fourth ventricle (Cl. Bernard), in
the sense that in some very small rabbits that survive bilateral
capsulectomy, puncture of the fourth ventricle does not induce
this diabetes.
XVI. The discovery of the physiological action of suprarenal
extract stimulated the efforts of chemical physiologists to isolate
its active principle. Frankel (1896) first prepared sphygmogenine,
followed by Abel's epinephrine (1898), 0. von Fiirth's suprarenine,
Vassale's paragangline. In 1901 Takamiue announced that both
Abel's epinephrine and von Fiirth's suprarenine were mixtures,
and that he had succeeded in isolating from the suprarenal capsules
a stable substance that crystallises, and is of constant chemical
composition, to which he gave the name of adrenaline. At the
same time, but independently, Aldrich also isolated the active
suprarenal principle in a crystalline form. F. Battelli discovered
a more practical and improved method of preparing the same
substance.
Takamine's adrenaline is a white powder, in small crystals,
very bitter, slightly soluble in water, faintly alkaline, so that it
i INTERNAL PROTECTIVE SECRETIONS 61
forms salts with different acids. It is not an alkaloid. It
oxidises readily, and is therefore strongly reducing, and can be
used as a developer in photography. Adrenaline has a marked
vaso-constrictor action. A cubic centimetre of O'l per cent solution
injected into the vein produces an increase in arterial pressure of
30 mm. Hg in a dog that weighs 8 kilos. When applied to the
conjunctiva it incites marked local ischaemia, of short duration, and
on this account is much used in ophthalmology. It has also been
resorted to successfully in severe catarrhal hyperaemia of the
external niucosae. According to Vassale the active suprarenal
principle also has a therapeutic action when introduced into the
stomach in gastric and intestinal atony.
In pursuance with the idea expressed above that the suprarenal
capsules consist of two distinct organs, and that maximal import-
ance must be ascribed to the medullary substance (chromaffine
tissue, capsular paragangliori), various attempts have been made
to determine which of the two substances, cortical and medullary,
is the seat of the active principle.
Salvioli and Pezzolini noted a marked difference in the
efficiency of the extract of medullary substance, which they found
to be greatly in excess of that of the cortical substance. Oliver
and Schafer (1895) had previously concluded from their experi-
ments that the active vaso-constrictor principle of the suprarenal
capsules is contained solely within the medullary substance. The
very weak effects which they sometimes observed after injection of
cortical extracts were due to post mortem processes of diffusion of
the medullary juice and other accidental contamination. Vassale's
recent work has fully confirmed these conclusions.
On the other hand, Langlois (1898), Swale Vincent (1896-97),
Biedl and Wiesel (1902), have shown that extracts of the extra -
capsular chromaffine tissue of the lower vertebrates (Amphibia,
Selachia) have the same action, while according to Biedl and
Wiesel the extracts may be made indifferently from the medullary
substance of the capsule, or from other accumulations of chrom-
affine tissue in these animals. Vassale therefore thinks it more
correct to give the name of paragangline to the active suprarenal
principle, which he prepared exclusively from the medullary sub-
stance of the suprarenal capsules.
It must, however, be noted that Vassale's paragangline is not
a chemically pure and crystallisable substance like Takamine's
adrenaline, but is an extract which contains the vaso-constrictor
principle in strong concentration, along with diastatic ferments,
and an abundance of lecithin, which has been demonstrated by
numerous observers in the medullary substance of the capsules
(Croftori, Alexander). Vassale himself admits " that adrenaline
is to paragangline as morphine is to opium."
Another series of recent researches was directed to solving the
62 PHYSIOLOGY CHAP.
question of the modifications suffered by the active suprarenal
principle when it is introduced into the body of the animal, as
also of its remote action when it is given many times in succession.
The following are some of the data : —
Langlois (1898) attempted to clear up the mechanism of the
destruction of the active principle of the capsule. According to
him it is rapidly destroyed in vitro by the action of oxidising
agents. When introduced into the arterial system, its action on
the blood pressure disappears in less than three minutes. The
pressure can be maintained at a constant height by successive
small injections of extract of the gland, at about three-minute
intervals. The disappearance of the effect coincides with the
return to normal pressure.
The duration of the effective period is in ratio with the
activity of metabolism. In the normal tortoise, in winter, the
action on the heart persists for about 3 hours; in the warmed
tortoise it disappears after 20 minutes. In cooled mammals the
increased pressure persists for 20-30 minutes.
The destruction of the active substance may occur in all the
tissues ; but the liver takes a preponderating part. In fact, the
fluid obtained by maceration of hepatic tissue attenuates the
activity of the suprarenal infusion more than the maceration
fluids of all other tissues. Infusion of a small quantity of the
extract into the mesenteric vein has no effect; while blood
pressure always rises if it is injected into a vein of the general
circulation. The blood from the hepatic veins of an animal that
has received an injection of the extract is less rich in active
substances than the blood of another region. Lastly, if the
hepatic circulation be cut out, the period of arterial hypertony
is prolonged.
Still the problem of the extremely rapid destruction of
adrenaline in the body does not seem, according to the most
recent work, to be definitely solved in Langlois' sense. Neujean,
indeed, held the methods by which Langlois attacked this problem
to be inaccurate, and concluded, after more exact research, that it
was still doubtful whether adrenaline is destroyed in the body
by oxidation.
Later on Patta (1905-7) showed that when adrenaline is injected
into the muscles or subcutaneous tissue, it does not produce rise
of blood pressure, as it would if injected into a vein, because its
absorption is considerably delayed by the vaso-constriction pro-
duced at the point of application ; it remains unmodified and
physiologically active for over two hours.
INTERNAL PROTECTIVE SECRETIONS 63
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Recent English Literature : — ,
R. H. CUNNINGHAM. Experimental Thyroidism. Journ. of Experim. Medicine,
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T. B. ALDRICH. Is Adrenalin the Active Principle of the Suprarenal Gland ? Amer.
Journ. of Physiol., 1902, vii. 359-368.
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the Action of Reducing Substances and other Poisons on the Cells of the
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Extract of the Suprarenal Capsule upon the Blood-vessels of the Rabbit's
Ear. Amer. Journ. of Physiol., 1903, ix. 252-261.
I
INTERNAL PROTECTIVE SECRETIONS 65
S. J. MELTZER and J. AUER. The Influence of Suprarenal Extract upon Absorp-
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J. MALCOLM. On the Influence of Pituitary Gland Substance on Metabolism.
Journ. of PhysioL, 1904, xxx. 270-280.
W. B. DRUMMOND. The Histological Changes produced by the Injection of
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D. NOEL PATON and A. GOODALL. Contributions to the Physiology of the
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W. W. HAMBURGER. The Action of Extracts of the Anterior Lobe of the
VOL. II F
66 PHYSIOLOGY CHAP, i
Pituitary Gland upon the Blood Pressure. Amer. Journ. of Physiol., 1910,
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C. H. H. HAROLD and M. NIERENSTEIN and H. E. ROAF. The Influence of the
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TRANSLATOR'S NOTE. — See also " Internal Secretion and the Ductless Glands,"
by Swale Vincent (Arnold, 1912), an invaluable resumt of the history and literature
of this subject.
CHAPTER II
EXTERNAL DIGESTIVE SECRETIONS
CONTENTS. — 1. Structure of salivary glands : cranial and sympathetic inner -
vation. 2. Nervous mechanism of secretion in salivary glands. 3. Cytological
changes in secretory epithelium during rest and secretion. 4. Selective activity
of salivary glands. 5. Chemical analysis of salivary glands and the various
kinds of saliva. 6. Structure of pancreas. 7. Innervation and mechanism
of its secretion. 8. Pancreatic juice. 9. Internal function of the pancreas.
10. Factors concerned in internal pancreatic secretion. 11. Structure of gastric
mucosa and glands. 12. Innervation. 13. Gastric juice and the cells which secrete
it. 14. Zymogens which give rise to the gastric enzymes. 15. Intestinal glands.
16. Succus entericus. 17. Mechanism of intestinal secretion. 18. Structure of the
liver. 19. Secretion of bile in digestion and fasting. 20. Influence on secretion
of changes in hepatic circulation. 21. Chemical constituents of bile. 22. Origin
and metabolic activity of hepatic cells. Bibliography.
FROM the group of glands which have no excretory duct, and
can only serve for internal secretion, we must distinguish the
group that are provided with excretory ducts, and are therefore
capable of external secretion, their products being poured out into
the gastro - intestinal canal. The principal function of these
secretions is that of chemical and physical transformation of
the ingested food, so as to render it fit for absorption and assimila-
tion, and thus to repair the losses perpetually sustained by the
tissues during the exercise of their functions.
These organs of external digestive secretion may histologically
be divided into three groups : (a) acinous glands, forming distinct
organs (salivary and pancreatic) ; (&) tubular glands, scattered in
the depth of the mucosa of the digestive tube (buccal, gastric,
and intestinal) ; (c) glands with branching tubes, grouped into a
large organ which forms the liver.
The external secretion, which (with the exception of the
biliary secretion) is the chief function of these organs, does not
exclude them from serving for internal secretion also ; but this
subject will be discussed in a subsequent chapter, the better to
appreciate its nature and physiological significance.
I. The excretory ducts of three principal pairs of glands which
manufacture and secrete Saliva open into the buccal cavity.
From their position these were termed parotid, sub-maxillary, and
67 F 1
68
PHYSIOLOGY
CHAP.
of puppy. (Lavdowsky.)
•n.
sublingual. They are glands of the racemose type, i.e. they
consist of acini, which are more or less saccular or tubular in
shape, their cavities or alveoli communicating with one another
by one or more branching excretory
ducts. The acini are surrounded by
a basement membrane consisting of
a network of flattened, nucleated,
branching cells, the meshes of which
are occupied by a delicate homo-
geneous substance. Inside the base-
ment membrane (Fig. 18) the secreting
cells form an epithelial lining which
bounds the alveolar cavity. The acini
are united into lobules, either by
blood-vessels or by loose connective
tissue, which contains many lymph spaces and a rich network
of blood capillaries.
Two kinds of secreting cells can be distinguished in the alveoli,
the serous or albuminous, and the mucous (Heidenhain). The
serous cells, which secrete
a thin fluid containing
serum - albumin, exhibit
in the resting state a
protoplasm so richly infil-
trated with granules that
the nucleus is obscured
and becomes invisible.
The mucous cells, which
secrete a fluid that is ropy
from the large amount of
mucin, are large, clear,
and spheroid when the
gland is resting. They
almost fill the alveolar
cavity, their nuclei being
invisible because they lie
close to the basement
membrane, and are
pressed against it (Fig. Fi
19). When all the alveoli
of a gland are lined with
albuminous cells (e.g. the
parotid in man and almost all mammals, the submaxillary of rabbits,
and certain glands that are scattered in the buccal mucosa), the
gland, as a whole, is termed albuminous; when the alveoli are
lined with mucous cells alone (e.g. part of the submaxillary in man,
and the sublingual in all animals, and many simple buccal glands)
.. 10.— Section of part of human submaxillary gland.
(Heidenhain.) On the right, a group of mucous alveoli
with demilunes of Giannuzzi ; on the left, a group of
serous alveoli.
II
EXTERNAL DIGESTIVE SECRETIONS
69
the gland is termed mucous ; when the alveolar walls are constructed
partly of mucous, partly of albuminous cells (e.g. the submaxillary
and suborbital of many mammals, part of the submaxillary in
man, and the majority of the scattered buccal glands), the gland,
as a whole, is termed mixed. In this case the albuminous glands
occupy a marginal position, and usually form little crescentic
masses known as the demilunes or crescents of Giannuzzi (Fig. 19).
The epithelial cells which line the intercalary and interlobular
excretory ducts are quite different from the secreting cells. The
ductules of lesser and medium calibre are lined with flattened,
cubical, striated cells ; the larger ducts with columnar, epithelial
Fio. 20. — A, section of alveoli from human sublingnal gland. Silver chromate method. (E.
Miiller.) I, lumen of intra-alveolar excretory ducts, stained black, and terminating in diverti-
cula which penetrate into the cells of the alveoli ; h diverticula penetrating into crescent cells.
B, section of alveolus from dog's submaxillary gland. Silver chromate method. (G. Retzius.)
Shows diverticula of excretory ducts extending into crescents of Giannuzzi. Also very fine
varicose nerve fibrils which form a network with large meshes between the alveolar cells.
cells. If the ducts are injected before making a microscopical
preparation, or treated with Golgi's method, which stains the
entire system of excretory channels a uniform black, the lumen
can be followed into the alveoli, and is seen to end in terminal
diverticuli, which penetrate between the cells, and enter for a
short distance into the protoplasm (Fig. 20, A, B).
Both the serous and the mucous salivary glands are supplied
by two kinds of nerves, those of cranial and those of sympathetic
origin. The former, for the submaxillary and sublingual glands,
originate in the roots of the facial nerve as the chorda tympani,
unite with the lingual branch of the fifth nerve, and then run
through the submaxillary ganglion to the parenchyma of the
gland. For the parotid, the cranial fibres from the glosso-
pharyngeal nerve run through Jacobson's nerve, the small super-
F 2
70 PHYSIOLOGY CHAP.
ficial petrosal, and the otic ganglion, and on reaching the auriculo-
temporal branch of the fifth nerve penetrate into the gland. The
sympathetic fibres run in the cervical sympathetic to the superior
cervical ganglion, accompany the carotid artery, and penetrate with
its branches by the hilurn to the interior of the three glands.
The nerve fibres are partly medullated, partly non-medullated.
Some supply the muscular sheath of the vessels, others the gland
cells ; the former are vasomotor, the latter secretory fibres. These
last, mostly as non-medullated fibres, perforate the basement
membrane of the acini, and terminate between the alveolar cells in
a free arborescence of the finest varicose fibrils (Fig. 20, B.).
Paladino (1872) observed direct terminations of the nerve fibres in
the gland cells of the salivary gland of dogs, solipeds, and man.
He further described intraglandular gangliated plexuses in the
submaxillary of the dog and of man.
II. It is evident that the salivary secretion is directly under
the control of the nervous system. The mere mental image of any
sapid substance, the sight or smell of a favourite food, is sufficient,
in vulgar parlance, " to make the mouth water." Stimulation of
the abdominal fibres of the vagus, in nausea, incites a copious flow
of saliva, principally during the reflux of food from the stomach
to the extremity of the oesophagus, which precedes vomiting.
To these facts of common observation which are within 'the
reach of all, we can add others, arrived at by physiological experi-
ment. The salivary secretion can also be excited by centripetal
stimulation of some of the sensory nerves, e.g. the central end of
the vagus or sciatic in a curarised dog (Owsjannikow). Electrical
excitation of a given area of the cerebral cortex (the so-called
centre for facial movements) promotes secretion (Landois, Lepine,
Bochefontaine), etc. It is interesting in this connection to note
that among the forms of partial epilepsy there is one in which the
fits are characterised by an enormous secretion of saliva
(Emminghaus).
A remarkable contribution to the more exact knowledge of
reflex excitation of the salivary secretion was made by Pawlow
and his co-workers (1904). The extraordinary aptness of these
reflexes is shown by a number of experiments, the most important
of which may be briefly summarised : —
If some quartz pebbles are introduced into the mouth of a dog
with a salivary fistula, the animal, after turning them over with
its tongue, lets them drop out without any flow of saliva, or at
most a few drops only, being excited. If, on the contrary, the
same stones are introduced into the dog's mouth in the form of
powder, so that it cannot push them out with the tongue, saliva
at once flows freely and carries away the quartz dust.
Dry, solid food produces an abundant secretion of saliva ; fluid
aliments, which already contain enough moisture for deglutition,
ii EXTEENAL DIGESTIVE SECKETIONS 71
excite much less. Strongly irritating substances, e.g. acids, salts,
etc., determine a copious flow of saliva, by which they are diluted
and their irritating action reduced. The saliva secreted under
these conditions is watery, and contains little mucin.
Excitation of the secretory centres of the salivary glands may
occur not only from stimuli in direct contact with the mucous
membrane of the buccal cavity, but also from excitation at a
distance, by the action of various stimuli on the different sense
organs, e.g. nose, eye, ear. Since it is impossible to find any other
explanation for this kind of stimulation, Pawlow calls it a
psychical excitation. If, e.g., a hungry animal is shown a bit of
bread or other food, a secretion results, while there is absolutely
no response on showing it to another that has eaten to repletion.
If some food or other substance that provokes nausea is shown the
dog several times in succession, the reaction is lessened till it dies
out. Yet if a little of the nauseous substance which no longer
evokes secretion is placed in the mouth, the first response reappears,
and lasts for a certain time.
The smell or other external sign of food is enough to determine
secretion. If, e.g., the hand, smelling of meat, is presented to the
dog, a flow of saliva is excited. If an acid has once been coloured
black, the sight of any black fluid will provoke secretion, assuming
of course that the black acid was introduced into the animal's
mouth on at least one occasion.
According to Malloizel's observations (1902) on dogs with a
permanent fistula, the reflex secretion of saliva is specific for
different peripheral stimuli. Thus the saliva excited by the action
of salts, sulphate of quinine, or sand, is thin and contains less than
1 cgrm. of mucin in 6 c.c. of saliva : the saliva excited by raw meat,
on the contrary, is very viscid, containing 1-2 cgrm. of mucin in
1 c.c. of saliva ; that excited by sugar is between the two. Henri
and Malloizel further found that the diastatic activity of reflexly
excited saliva varies with different stimuli ; it is greater for meat
than for salts.
The sight or smell of different substances, again, excites a
specific secretion of saliva. Section of the chorda tympani
abolishes every secretory reflex, while section of the sympathetic
has no effect.
All these, like the preceding, are phenomena of reflex secretion,
in which the excitation travels along the afferent paths to the
centres, which then transmit it by the efferent secretory paths.
Certain experiments of 01. Bernard, Eckhard, Loeb, Griitzner,
and Chlapowski show that the centres of salivary secretion are
localised in the bulb, probably at the origin of the facial and
glosso-pharyngeal nerves. In fact, when the bulb is separated
from the spinal cord by a cross-section, salivary secretion can no
longer be excited by the same means. On electrical excitation, or
72 PHYSIOLOGY CHAP.
better on pricking the bulb in the vicinity of these centres,
secretion is at once aroused.
Kohnstamm (1902) found that division of the nerve fibres that
arise in the chorda tynipard and pass by the lingual to the sub-
maxillary gland, was followed by degeneration of a group of cells
in the bulb near the facial nucleus, mostly on the opposite side, to
a less extent on the same side as the operation. The nerve fibres
that come in the submaxillary gland originate in these cells.
Hence the latter are termed by the author the salivatory
nucleus.
The interpretation of the effects of the so-called scialagogues is
doubtful. These consist in a series of toxic or medicinal substances
which, when injected under the skin or into the veins, promote a
more or less copious secretion of saliva. The principal are pilo-
carpine, physostigmine or Calabar beans, curare, etc. Do these
substances induce a flow of saliva because they directly or reflexly
excite the secretory nerves, or because they act by modifying the
metabolism of the secretory cells ? It is probable that their action
is distributed throughout the system, and that the effect is
analogous to the secretion of saliva produced in asphyxia by the
accumulation of carbonic acid and the other katabolic products
of metabolism in the blood.
As contrasted with the substances which produce ptyalism, we
have another group, headed by atropine and daturine, which
arrest all salivary secretion (Keuchel). These substances act
particularly by paralysing the cranial secretory nerves. The flow
of saliva excited by pilocarpine can be arrested by atropine, and,
vice versa, the arrest of secretion by atropine can be antagonised
by pilocarpine and also by muscarine.
The process of secretion, more particularly in the submaxillary
gland, which is the most accessible to experiment, has from 1851
to the present day been the subject of constant and varied experi-
ments (especially by Carl Ludwig and his school) which have
yielded very important results. The most significant of these data
and the deductions to which they lead can be summarised as
follows : —
(a) If after introducing a cannula into Wharton's duct in the
dog, the lingual branch of the fifth nerve (or simply the chorda
tympani, which runs from the facial to the lingual branch and
gives off fibres to the gland) is cut, all salivary secretion ceases,
and no saliva flows from the end of the cannula (Ludwig). This
proves that secretion of saliva is normally dependent on a reflex
nervous act conveyed to the gland by the fibres of the chorda
tympani. If the peripheral end of the lingual nerve (or the
chorda tympani) be electrically excited an abundant secretion of
saliva follows, which will in a few minutes reach, and even exceed,
the volume of the gland (Ludwig). This shows that stimulation of
ii EXTEENAL DIGESTIVE SECRETIONS 73
the nerve excites a stream of fluid which passes from the blood
capillaries to the lymph spaces, and thence to the glandular spaces,
the material contained in the gland not being sufficient for such
an abundant flow of saliva.
(6) Between the excitation of the nerve and the appearance
of the secretion there is an appreciable period of latent stimula-
tion, which may vary between 1-2 seconds (Hering) and 24 seconds
(Ludwig).
The secretion persists for a short time after the close of
stimulation. This period, known as the after-effect, increases in
proportion with the excitability of the nerve (Ludwig). In fact,
if the stimulation lasts only for a short time, so that the nerve
is not excessively fatigued, the after-effect lasts longer. These
phenomena confirm the dependence of the secretion upon the
activity of the secretory nerve.
(c) Excitation of the cervical sympathetic (or of the
sympathetic fibres that accompany the carotid and run to the
submaxillary gland) also produces a secretion of saliva, although
much more slowly and in smaller quantities. Moreover, while
the saliva obtained by stimulation of the cranial nerve is watery
and slightly viscid, and shows under the microscope very few
salivary corpuscles and granulations, the saliva secreted by excita-
tion of the sympathetic is very dense, viscid, ropy from large
quantities of mucus, and contains numerous corpuscles and
granulations (Eckhard, 01. Bernard).
(cT) The blood -supply of the gland is modified in contrary
directions by stimulation of the chorda tympani and of the
sympathetic. In the former it is enormously increased by active
vascular dilatation, in the latter diminished by active constric-
tion (see Vol. I. p. 342 et seq.). It cannot be denied that the
marked difference in quantity, density, and viscidity of the
saliva obtained on exciting the two kinds of nerves depends — at
least in part — on the varying blood-supply to the gland in the
two cases. The difference is much reduced if the gland be filled
with blood by a brief stimulation of the chorda tj'inpani before
exciting the sympathetic. In this case excitation of the sym-
pathetic produces a more copious and less viscid saliva.
Burton -Opitz (1904), using Hiirthle's haemodrometer, esti-
mated the velocity of circulation in dogs in the branches of the
external jugular vein, and found it normally very low. By
stimulating the intact chorda tympani it was possible to increase
it from two- to six-fold. Stimulation of the sympathetic, on the
contrary, determined an almost complete arrest of the circulation.
Longer stimulation of the vasoniotors fatigues them, and the
circulation then returns to the normal rate, even if the stimula-
tion be continued.
(e) The saliva secreted after stimulation of the cranial nerve
74 PHYSIOLOGY CHAP.
has a temperature 1'5° C. higher than that of the arterial blood
which traverses the origin of the carotid. The difference in the
two temperatures is greater in proportion as the flow of saliva
from the cannula inserted in Wharton's duct is more rapid
(C. Ludwig and A. Spiess). This proves that during secretion
the oxidative processes, or the respiration of the secretory cells
of the gland, increased — so that much energy is liberated in
the form of heat. This is not contradicted by the fact first
noticed by Bernard to the effect that during the stimulation of
the chorda the blood flowing back from the gland assumes the hue
of arterial blood, because the velocity of the blood current in the
gland, owing to the vascular dilatation, increases more rapidly
than the consumption of oxygen.
(/) The presence of oxygenated blood undoubtedly favours
secretion. If the principal vein that leaves the submaxillary
gland be occluded while the chorda is stimulated, secretion gradu-
ally ceases, recommencing after the vein has been freed, with
sufficient lapse of time for the black asphyxial blood collected in
the vessels of the gland to be replaced by red arterial blood
(Ludwig). The rate of flow of saliva thus depends not only upon
the amount of nutritive materials that reach the gland, but also
upon the quantity of oxygen, i.e. the arterial character, of the
blood circulating in it.
Barcroft (1901) noted in dogs that during the secretion pro-
duced by stimulation of the chorda the amount of oxygen taken
up by glandular tissue from the blood is three or four times
greater than in the resting gland. After injection of atropine
there is no longer any increased assimilation of oxygen on
stimulating the chorda, while more CO2 is still given off, for a
time at any rate.
(g) If the cranial and the sympathetic nerves of the sub-
maxillary are simultaneously excited, secretion is at first aug-
mented, but soon becomes slower than when one nerve alone
is stimulated, until finally it is almost entirely suspended
(Czermak). This effect is due to interference of excitation in the
two nerves, as well as to functional predominance of the con-
strictor fibres over the dilators in the nerves of the gland, as
shown by von Frey (see Vol. I. p. 351).
(h} We have seen that secretion is arrested after section of
the chorda, even when the sympathetic is left uninjured. This
functional arrest is not permanent. After about 24 hours the
gland begins once more to pour out a continuous secretion of very
thin saliva, poor in organic substances. This phenomenon was
termed by Claude Bernard (who first noticed it) paralytic secretion.
It increases steadily in the first week : after that it slowly
diminishes, owing to the degeneration of the gland. After
excision of the submaxillary ganglion (according to Bernard)
ii EXTERNAL DIGESTIVE SECRETIONS 75
paralytic secretion always makes its appearance. It can also
be provoked by the injection of small doses of curare into the
glandular arteries. It ceases in apnoea, and increases in dyspnoea.
After heinisection of the cord, paralytic secretion appears in the
gland of the opposite side also (Heidenhain). The interpretation of
these facts is very doubtful. Langley believes that the excit-
ability of the central end of the chorda increases after section, so
that it reflexly influences the secretion of both glands.
(i~) A series of striking experimental data prove that the
salivary secretion excited by the activity of the nerve depends
essentially upon altered metabolism of the secretory cells, and
not on alteration of the blood-supply to the gland. Secretory
activity excited from the nerve persists for a certain time after
all the blood-vessels to the gland have been occluded, and even
after decapitation of the animal (Ludwig, Czermak, Giannuzzi).
On the other hand, when a mercury manometer is introduced into
the excretory duct of the submaxillary gland, and the chorda
tympani excited, secretion continues, even when the pressure in
the excretory ducts of the gland rises to a height considerably in
excess of that in the carotid artery. The pressure in Wharton's
duct may rise to 200 mm. Hg, while that of the carotids is not
above 122 mm. Hg. This shows that the stream from blood-
vessels to lymphatics, and from these to the glandular spaces, is
not merely independent of the pressure, but actually occurs
against the laws of filtration (Ludwig).
(&) We have already seen that the injection of even small
doses of atropine and daturine suffices to abolish the secretory
activity of the chorda tympani (Keuchel). But if the state of the
glandular blood-vessels is watched during stimulation of the nerve,
it is found that their active dilatation is in no way hindered by
atropinisation (Heidenhain). We must therefore assume that the
chorda contains secretory fibres as distinct from the vaso-dilators.
Atropine paralyses the former and leaves the latter unaffected.
(I) When a substance that paralyses the activity of the
secretory cells, e.g. a dilute solution of hydrochloric acid, or of
sodium carbonate, is injected into Wharton's duct, and the chorda
tympani subjected to prolonged stimulation, all secretion is
arrested and there is marked oedema of the gland from congestion
of lymph (Giannuzzi). This shows that the dilatation of the
arteries is capable of promoting the filtration of the lymph, but
not its penetration into the gland spaces.
(m) Unilateral excision of the chorda tympani in puppies has
as a remote effect a marked diminution in weight of the corre-
sponding submaxillary, which may amount to 50 per cent. There
is at the same time a reduction in the volume of the mucous cells
and the serous cells, which form the crescents or demilunes of
Giannuzzi (G. Bufalini).
76 PHYSIOLOGY CHAP.
All these phenomena relate to the secretory process in the
submaxillary gland of the dog, which has heen the subject of
innumerable researches. But the same facts (with slight differ-
ences) may be observed in other animals also. Thus in the rabbit,
the saliva that flows on excitation of the chorda and also that
from excitation of the sympathetic are limpid and fluid ; in the
cat, the first kind is more viscid than the second. But in both
cases excitation of the chorda produces copious secretion and
vascular dilatation, excitation of the sympathetic, scanty secretion,
and vascular constriction.
Gerhardt studied the histological changes consequent on
section of the secretory nerves on the salivary glands of rabbit,
and found substantial differences in the effects of dividing the
chorda and the sympathetic. In the former the protoplasm was
altered while the nuclei remained intact; in the second, on the
contrary, there were marked nuclear alterations with normal
protoplasm. The two kinds of histological change were never
observed in all the gland cells, but only in foci, without any
apparent regularity, partly in big nests, partly isolated. The
nuclear alterations from section of the sympathetic were not
confined to the side of the section but spread also, although to a
minor extent, to the opposite side.
The nervous mechanism of the other salivary glands is similar
in its general features to that of the submaxillary gland, on which
we have dwelt at length. Division of Jacobson's nerve or of the
small superficial petrosal nerve, or excision of the otic ganglion,
arrests the secretion of the parotid gland (Bernard, Schiff,
Heidenhain). Excitation of these cranial fibres produces in the
parotid the same secretory and vascular effects as that of the
chorda tympani in the submaxillary. The pressure measured in
Stensen's duct rises during stimulation to 106-118 mm. Hg.
The flow of blood from the gland is accelerated and assumes
the arterial hue (Heidenhain). The effect of stimulating the
sympathetic has, on the contrary, been much disputed. Some
deny it, others admit a simple constrictor effect on the parotid
vessels, others, lastly, assume a trophic influence upon the gland
cells, as distinct from the secretory influence (Heidenhain).
The sublingual gland is controlled by the same nerves as those
which regulate the secretion of the submaxillary. Stimulation of
the chorda tympani excites secretion from the sublingual as well,
but requires a stronger stimulus (Cl. Bernard, Heidenhain).
The stimulation of the sympathetic has no perceptible effect.
III. The most obvious proof that the secretory effect of
exciting the nerves is due essentially to their trophic influence
upon the metabolism of the secretory gland-cells, is shown under
the microscope in the marked changes which these cells undergo
during secretory activity. We owe to Heidenhain (1868) this
II
EXTEENAL DIGESTIVE SECEETIONS
77
fine discovery, which enables us, up to a certain point, to penetrate
to the interior of the cells, and to ascertain what cytological
phenomena accompany the process of secretion.
Pio. 21.— Babbit's parotid. Alcohol-carmine method. (Heidenhain.) A, resting state ;
B, after stimulation of cervical sympathetic.
Microscopic preparations of serous glands hardened in alcohol
and stained with carmine show in the resting state a colourless,
PIG. 22.— Orbital gland of dog. Alcohol-carmine method. (Lavdowsky.) A, resting state ;
B, maximal degree of change which the gland is capable of exhibiting in secretory activity.
clear, finely granular cytoplasm, and a nucleus that stains red,
with wavy outlines and no distinct nucleoli (Fig. 21, A). After
excitation of the secretory nerve, and when some cubic centimetres
of saliva have been given off, the cells visibly alter in character.
78
PHYSIOLOGY
CHAP.
Their total area diminishes from loss of clear cytoplasm; the
granular substance on the contrary increases, so that the cell
appears more clouded, the nucleus becomes rounded with more
regular outlines, and the nucleolus is plainly visible (Fig. 21, B).
Microscopic preparations of mucous glands treated in the same
way show in the resting state large clear cells with colourless
cytoplasm, which consists of a very tine filamentous network with
large meshes, filled with an amorphous, shining, mucinogenous
substance, which resembles small granules. The nucleus stains
with carmine ; it has no visible nucleolus, and is always situated at
Fio. 23. — Rabbit's parotid in fresh state. (Langley.) A, resting state ; B, after injection of
weak doses of pilocarpine ; C, after stimulation of cervical sympathetic ; D, after more
prolonged stimulation of this nerve.
the periphery or margin of the cell (Fig. 22, A). After prolonged
secretion excited by stimulation of the secretory nerves, the cells
appear much reduced from loss of the clear muciuogenous
substance, the cytoplasm stains, the nucleus is rounded, with a
distinct nucleolus which has moved to the centre of the cell
(Fig. 22, B).
The subject of these histological researches is (as Heidenhain
points out) not the living cell, but its dead body, altered, moreover,
by the technique of hardening and staining. Yet, since the
phenomena are so constant, we may safely conclude that the
living cells also are differently constituted in the resting and in
the active state, owing to the manufacture of secretion. Eecent
comparative researches on gland cells in fragments of living gland
fresh from the body, show that while their microscopic appearance
ii EXTEENAL DIGESTIVE SECKETIONS 79
differs widely from that described by Heidenhain, it lends itself
essentially to the same interpretation.
In the serous glands, Langley found that in the resting state
the secretory cells exhibit a protoplasm rich in granules, which
conceal the outline of the cells and the nuclei. After prolonged
secretion, caused either by injection of pilocarpine or by stimulation
of the nerve, the alveoli become smaller, and the granules gradually
disappear, especially in the outer zone which is covered by the
basement membrane; they collect in the inner zone, which
surrounds the lumen, and finally vanish, accumulating as secretion
in the cavities of the gland (Fig. 23).
Similar phenomena can be observed in fresh preparations of
the mucous glands. They are more conspicuous in the simple
than in the compound glands,
e.g. those of the frog's tongue,
placed as soon as excised in
physiological salt solution
(Biedermann). In the rest-
ing state the cells are full
of dark, highly refracting
granules, which often conceal
the nucleus ; during active
secretion, on the contrary, the
granulation practically disap-
j A , • FIG- 24.— Part of lingual gland of Rana esculenta,
pears, ana Wliat remains IS , in fresh state. (Biedermann.) A, resting state ;
collected at the inner margin ?orfhe0ri^mulation of sloss°-Pharyngeal nerve
(Fig. 24).
From these data we learn that a substance is formed during
the functional rest of both albuminous and mucous salivary glands
which disappears during activity, and passes into the secretion,
while the cell becomes swollen. This substance dissolves
in alcohol -hardened, carmine - stained preparations; in fresh
specimens, on the contrary, it appears in the form of small
granules.
These phenomena do not decide the important question
whether during the secretory process the living protoplasm of the
cells is utilised and converted into the materials of secretion, or
whether the secretion is produced by the living protoplasm as a
direct elaboration of the lymph absorbed from the perialveolar
lymph spaces. Heidenhain adopted the former view, and con-
cluded that the cells liquefy in consequence of their secretory
activity. According to him Giannuzzi's demilunes consist of cells
intended to replace those which break up. Against this theory is
the fact that karyokinesis is rarely seen during secretion, and that
if epithelial regeneration be present, it relates not to secretory
activity, but to the life cycle of the individual cells. The second
theory, which, as we have seen, was held by Johannes Mliller, and
80 PHYSIOLOGY CHAP.
adopted by Langley, is more probable, and harmonises with the
fact that, generally speaking, living cells in carrying out their
functions consume the chemical matters which they have
absorbed and elaborated, and only utilise their own protoplasm
when all other materials are exhausted.
IV. The important question of the specific property by which
the salivary glands select from the substances offered them by the
blood the constituents of an effusion that is quite unlike the blood
itself, has hitherto been treated only by a few authors, and that
incidentally. Novi (1888) estimated the amount of chlorine
contained in a sample of blood from the carotid and in one of
saliva, before and after injecting a 10 per cent solution of sodium
chloride into the jugular. He found that when the concentration
of the blood was thus increased, the rate of secretion increased
also. Novi further observed that the chloride content of the
saliva increased much more rapidly than that of the blood serum.
When, e.g., the chloride in the sodium increased from 100 to 155,
that in the saliva increased from 100 to 220. Langley and
Fletcher confirmed the observations of Novi, showing that dilute
solutions of sodium chloride, while they still augment the rate of
secretion, lower the concentration of the saliva.
Asher and Cutter (1900) on injecting sugar and urea showed
that sugar excites secretion only by causing hydraemic plethora,
and does not appear in the saliva ; urea, on the contrary, excites it,
and partly reappears in the saliva.
According to Aducco these different effects show that the
production of the secretion depends not only upon the physical
and chemical constitution of the circulating substances, -but also
upon their effect on metabolism. Thus urea, which is a katabolic
product, and is not present in the normal secretion of the gland, is
capable of activating it and of stirring up the secretory cells to
more work ; while sugar does not pass through the gland (provided
the physiological limits are not exceeded), and only acts indirectly
upon the secretion, i.e. by augmenting the mass and the dilution
of the blood.
This explanation of the phenomenon appears to us inadequate.
If under th'e said experimental conditions it is a fact that the
increased sugar content of the blood increases the flow of saliva,
under other conditions, e.g. in experimental hyperglycaemia and
in diabetes in general, the secretion of saliva is very scanty, much
below the normal.
Many salts when introduced into the vascular circulation
appear rapidly in the saliva (potassium iodide, lithium citrate, etc.) ;
others, on the contrary (bile salts), which are eliminated by all
other glands when present in the blood do not pass through
the salivary glands.
In regard to the selective capacity of the salivary glands,
ii EXTEENAL DIGESTIVE SECEETIONS 81
U. Loinbroso, on injecting into the dog's jugular a large quantity
of pancreatic secretion collected directly from a Pawlow's fistula,
noted that the saliva did not (like other digestive secretions)
acquire any of the enzymatic properties characteristic of pancreatic
juice : bile, e.g., acquires an intense lipplytic activity, which
persists for several days after the injection.
V. Chemical analysis shows the presence of a number of
proteins in the salivary glands, among them a nucleo- protein
(Hammarsten), a substance which forms a special enzyme known
as ptyalogen, or the zymogen of ptyalin (in the albuminous glands),
mucinogen, the mother-substance of mucin (in the mucous glands),
and the mineral salts of blood serum. With prolonged stimulation
of the secretory nerves to the albuminous and mucous glands, both
the ptyalogen and the mucinogen disappear to form again during
the resting period.
The increase of volume and weight in the salivary glands
during rest depends largely upon the greater amount of proteins
absorbed, since this increases the nitrogen content. Glands sub-
jected to prolonged stimulation contain 7 per cent less solids than
the resting gland, but this difference depends partly on the
greater amount of water absorbed by the gland during secretion,
in analogy with the conditions that prevail during muscular work.
As regards chemical composition we must distinguish the
mixed saliva or total secretion from the simple and compound
salivary glands that open into the buccal cavity, from the separate
salivas secreted from the albuminous, mucous, and mixed glands
respectively.
Mixed saliva is colourless, with no smell, opalescent, viscid,
faintly alkaline in reaction ( = 0'097 per cent Na2C03) or neutral,
its specific gravity being 1002-1006 in man (1007 in dog). It
is remarkable that the osmotic pressure of saliva is considerably
less than that of the blood. Nolf (1900) showed that the
saliva spontaneously secreted from the dog's submaxillary has
a freezing-point from - O'll to - 0'27, and that secreted during
stimulation of the chorda freezes at - 0'19 to - 0'4. The osmotic
pressure of dog's blood, on the contrary, corresponds to a lower-
ing of the freezing-point = - 0'549 to - 0'605 (see Vol. I. pp.
142, 148).
If left to itself the mucin of the saliva precipitates, along with
the old epithelial cells thrown off by the buccal epithelium. It
also becomes turbid from the precipitation of the calcium carbonate
dissolved in the saliva in the form of bicarbonate. The microscope
shows the so-called salivary corpuscles, which resemble small
leucocytes with granulations that exhibit lively Brownian
movements.
It is not possible to obtain an exact estimation of the total
quantity of saliva secreted daily ; approximate figures only can be
VOL. II G
82 PHYSIOLOGY CHAP.
given. There are marked variations in the different species of
animals on which observations have been made. While the horse
secretes 14*2 grrns. saliva to every gramme of gland per hour,
during mastication, the calf only secretes 8 grms. (Tuczek). From
this point of view it seems probable that the salivary glands are
the most active. In man the secretion of saliva amounts to some
1500 grms. per diem.
The organic components of mixed saliva are : —
(a) Mucin, which precipitates with acetic acid or alcohol, and
is derived from the mucinogen of the glandular epithelium.
(b) Ptyalin, an enzyme discovered by Leuchs in 1831. It is
derived from the ptyalogen of the gland-cells, and is constant in
the saliva of man, horse, rabbit, and of herbivora in general, while
it is regularly absent in that of dogs and of carnivora in general
(Hoppe-Seyler). It is an amylolytic enzyme, the action of which
will be discussed in treating of buccal digestion.
The existence of a pro-enzyme of ptyalin (ptyalinogeri) corre-
sponding to what exists for the gastric and pancreatic enzymes
(propepsin and protrypsiri), was demonstrated by Miss Latimer.
On washing the salivary glands repeatedly with water and chloro-
form, they are freed from the active ptyalin which they contain ;
on then treating the gland with a dilute solution of acetic acid an
extract capable of saccharifying starch is obtained.
(c) A globulin that precipitates with heat, on addition of
mineral acids and also on passing a current of carbonic acid.
(d) Sulphocyanide of potassium or sodium, which is frequent
but not constant in human saliva in minute quantities of 0'016-
0'084 per thousand (Oehl), according to others in an average
quantity of 010 per thousand (Jacubowitsch). It may possibly
be formed in the mouth by the action of special microbes.
According to Kriiger it increases in smokers.
Grober's latest investigations (1901) show that the sulpho-
cyanide is not formed by decomposition of saliva ; its elimination
probably depends on the general protein metabolism, since it is
eliminated little or not at all by persons suffering from cachexia.
(e) Traces of urea, and, in abnormal conditions, of leucine and
of lactic acid.
The inorganic compounds consist of small quantities of chlorine
and phosphoric acid combined with potash, soda, lime, and
magnesia ; small quantities of sodium carbonate and abundant
quantities of sodium chloride.
The amount both of water and of solids in the saliva may
fluctuate considerably with food or abstinence, or other changeable
factors. We must confine ourselves to citing the results of
Hammerbacher's analyses, which are of the mixed saliva (1000
parts) of a young healthy man, and which agree perfectly with
those of Frerichs :
ii EXTEKNAL DIGESTIVE SECEETIONS 83
Water 994-203
Solid substances .- 5 '797
Epithelia and muciii . . . . . 2-202
Ptyalin and globulin . . . -. .. '-..'. T390
Inorganic salts . . .... . . 2 205
Sulphocyanide of potassium ... .... 0041
The same author found in 1000 parts of ash of human saliva :
Potassium . . 457'2
Sodium - .... 95-9
Ferric oxide . .... • . >. . 50'1
Magnesium . . . . . ... . T5
Sulphuric acid 63 -8
Phosphoric acid . ' 188'5
Gxhlorine . . ^ 183-5
In order to obtain and analyse separately the saliva of the
respective glands, the excretory ducts of Stensen and Wharton
can be syringed with special metal cannulae (Ordenstein, Oehl,
Eckhard) in man, and on dogs artificial fistulae of the same canals-
can be established.
The parotid saliva of man is thin from absence of mucin, but
it becomes ropy and viscid if the secretion is scanty ; the reaction
is alkaline ; it is rich in ptyalin even in the newborn ; contains
but little globulin. Constituents, 9 9 '5 per cent water, 0'5 per
cent solids, of which 0'2 per cent are alkaline chlorides, 0'2 per
cent carbonate of lime, and 015 per cent organic compounds, of
which 0'03 are sulphocyanide (Oehl).
The submaxillary and sublingual saliva in man is more watery,
more alkaline, more viscid, because it contains mucin : it has a
weaker diastolic action, because it contains less ptyalin ; and the
amount of sulphocyanide is less (Oehl).
Lastly, the submaxillary and sublingual saliva differs under
the microscope from parotid saliva, in containing many more
salivary corpuscles and shed mucous cells.
Cohnheim's method is the best for extracting a tolerably pure ptyalin
from saliva, (a) The saliva is strongly acidified with phosphoric acid (using
2 litres of mixed saliva) ; (b] the filtrate is then made alkaline with milk of
lime, which forms a precipitate of tribasic phosphate of lime and brings
down the ptyalin ; (c) the precipitate is collected on a filter and washed
with distilled water, which dissolves ptyalin ; (d) 5-6 volumes of alcohol are
added to the filtrate, when a flocculent precipitate is formed ; this is dried
in vacua ; (e) this precipitate is redissolved in distilled water, filtered and
reprecipitated with absolute alcohol ; the precipitate is dried, and consists of
purified ptyalin.
To show the presence of sulphocyanide of potassium in the saliva, add a
few drops of perchloride of iron, after acidifying with dilute hydrochloric
acid. The fluid turns more or less blood-red, according to the amount of
sulphocyanide contained in. the saliva (Oehl).
Solera's reaction is based on the i'act that the sulphocyanide separates
iodine from the iodic acid. On adding starch paste and then iodic acid to
the saliva, the iodine is liberated, and gives a blue colour with starch.
G 1
84
PHYSIOLOGY
CHAP.
VI. The Pancreas is a long gland, of irregular prismatic shape ;
its external secretion is conveyed to the duodenum by the canal
or duct of Wirsung, which runs along the entire length of the
gland, buried in its substance. Its size and weight differ consider-
ably in different individuals. It is 12-13 cm. long, with a
maximum diameter of 12-25 mm. According to Krause, it weighs
66-102 grms., but Meckel gives a maximum weight of 180 grins.,
and Sommering a minimal weight of 45 grms. Its specific gravity
is 1-046.
From its structure the pancreas must be regarded as an
acino-tubular gland, resembling the salivary glands, but with
•:"
Fio. 25. — Section of human pancreas. (Bcihm and V. Davidoff.) D,'principal duct; C, connective
tissue; A, alveolus or acinus; c.c, centro-acinar cells of Langerhans ; P, commencement of
duct ; p, small alveolus without central cells.
lobes and lobules more loosely knit together by connective tissue.
The secretory alveoli consist of short tubules, which in a section
resemble rounded acini. The primary and secondary ducts are
lined with simple columnar epithelium, the cells of which become
lower in the small ducts, till where these arise in the alveoli
they are reduced to narrow, flattened, spindle-shaped cells (Fig. 25).
The number of ducts in the pancreas is not constant even in
a series of the same animals. In man they are usually two, the
principal, or duct of Wirsung, and the accessory, or duct of
Santorini. The latter may be absent (Hess), in any case it is
always very minute in the adult, while in the early stages of
development it is larger than Wirsung's duct. In the dog there
are invariably two ducts, and in a certain number of cases (30 per
11
EXTERNAL DIGESTIVE SECRETIONS
85
cent) a third (Hess). In the rabbit there is a secondary duct besides
the duct of Wirsung, but it is of no importance in the adult ;
U. Lombroso (1907) showed that ligation of the principal duct
alone causes diffuse- alterations in all the organs, co-extensive with
those observed when the secondary duct is also occluded.
When freshly examined, the secreting cells at the end of the
alveoli show a clear, homogeneous, outer zone, covered with the
basement membrane, and a granular, somewhat clouded, inner
zone, which is turned towards the lumen. In very fresh prepara-
tions the granules extend over the whole of the cells, but if
the preparation is cooled they are packed towards the lumen.
In quite fresh preparations, again, the nucleus is invisible, or
scarcely seen. In carmine
preparations only the outer
zone and the nucleus stain
(Fig. 26).
In the middle of the al-
veolus Langerhans (1869)
discovered spindle-shaped
cells with a homogeneous
body, sharp outline, and
a large clear nucleus,
known from their position
as the centro-acinar cells.
Saviotti, Boll, Ebner, v.
Frey, Giannelli and many
others, showed by system-
atic investigation of various kinds of animals that these cells
are constant in all vertebrates. Such centro-acinar cells are more
numerous at the neck of the alveolus than at its base, where they
may be entirely absent.
The nature of these cells has been the subject of much dis-
cussion. Langerhans, Saviotti, Heidenhain, regard them as
epithelial cells. Pfliiger takes them to be nerve cells. Many
authors have supposed them to be connective tissue ; but all these
surmises have now been abandoned, and after the histogenetic
studies of Laguesse and his pupils, their epithelial character is
generally admitted.
According to Renaut and Laguesse the centro-acinar cells are
the essential factors in all the changes of form that occur within
the gland. They also participate in the external secretion.
In addition to the epithelial cells which constitute the alveolar
gland proper (acinar cells, centro-acinar, epithelial cells of ducts)
the pancreas of all vertebrates presents areas of tissue or com-
pact structures, which are distinct in character from the alveoli.
They stain much less freely with ordinary methods; in some
cases the individual cells have no sharp outline but resemble a
G 2
FIG. 26.— Pancreas of fasting clog. Alcohol-carmine
method. (Heidenhain.)
86
PHYSIOLOGY
CHAP.
protoplasmic mass, in which a number of nuclei are arranged
irregularly, so that for a long time these cells were thought to
be lymphoid. Kecent research, has, however, shown them to be
epithelial. According to some authors these epithelial bodies are
destitute of excretory ducts ; but they invariably exhibit a number
of tortuous blood-vessels which in certain cases (Ktihne and Lea)
assume the form of glomeruli. They are generally known as the
islets of Langerhans (Fig. 27).
The special significance of these islets has recently been much
FJG
i. 27. — Section of rabbit's pancreas. (Marassini.) The periphery shows a number of glandular
acini, which are darker in colour ; at the centre is a large islet of Langerhans of a lighter
'colour, composed of cells with indistinct outlines.
discussed. Many observers conclude from their morphological
characters (absence of ducts, abundance of blood-vessels) that they
are responsible for the internal secretion of the pancreas, while
others claim that the alveoli, too, participate in this function.
As regards the relation between the islets and the alveoli,
Lewaschew (1886) suggested that the islets represent phases in
advancing exhaustion of the secreting alveoli. According as the
latter are more or less fatigued, they exhibit cells which ap-
proximate to the characters of the islets or the acini. He
supported his hypothesis by observations which showed that the
islets are more numerous in the pancreas of over -fed animals,
and during the action of pilocarpine. Lewaschew's theory was
adopted, as regards the possible derivation of islets from alveoli,
by Dogiel, Perdisgeat and Tribondeau, Dale, Laguesse, and many
others.
Laguesse, however, modified its physiological interpretation,
ii EXTERNAL DIGESTIVE SECRETIONS 87
and regards this process as an alternation between the external
and internal secreting conditions of pancreatic tissue, which is
necessary to enable the organ to accomplish its double function.
The theory of the development of alveoli into islets, and
vice versa, was soon contested.
Vassale (1891) first showed that after ligation of Wirsung's
duct in rabbit, the islets remain, while the alveoli disappear.
Massari (1898) found that in eels the islets were constant and
invariable, without any true transitional forms. Immediately
after, Giannelli, Renaut, Diainare, Jacotsky, W. Schultze, Opie,
and others, on repeating the experiments of Lewaschew's school
(hyperalimentation, pilocarpinisation, inanition, etc.), failed to find
any constant difference in the number and appearance of the
islands, in the various animals experimented on. Since that
time the theory of Lewaschew and Laguesse has been unanimously
abandoned.
It remained to be seen whether the islands were in com-
munication with the excretory ducts. The results obtained by
certain authors who attempted to solve the problem by injecting
the ducts with coloured solutions which are readily recognised
under the microscope, are directly contradictory. Thus Lewaschew
(1886), Mankowski (1901), asserted that the injected substance
penetrates to the islets. V. Ebner (1872), G. Rossi (1902), and
others affirm that it never reaches the islets. But it must be
noted that injection by the ducts does not always reach the whole
of the alveoli, as observed by Rossi. These negative results have
therefore no decisive value.
Simple histological examination, on the contrary, does tend to
support the hypothesis of communication between the islets and
the excretory ductules. Laguesse, in a fragment of human pan-
creas, noted that out of 56 islets followed in serial section, only
4 were entirely independent. Of the other 52, many were either
in direct relation with the excretory system, or were joined to it
by the alveoli.
A highly important detail, as to which opinions differ, is the
existence of a connective capsule, surrounding the islets com-
pletely, and separating them sharply from the alveolar tissue.
Renaut (1879) pointed out a reticulum enclosing the islets, as
did also Opie and Pugnat. On the other hand, Gibbes, Diamare,
and Hansemann denied these observations. To solve the problem
Marshall Flint (1903) employed tryptic digestion, which spares
this capsule ; and decided that it existed.
Laguesse also admitted it, but stated that the capsule
(membrana propria) does not completely surround the islets, which
contract relations with the excretory system at the points at
which they are not invested.
Golgi's method demonstrates the origin of the excretory
G 3
88
PHYSIOLOGY
CHAP
ductules within the pancreatic alveoli: like the salivary glands,
they stain a uniform black. As shown in Fig. 28, the excretory
duct sends lobular branches to these ductules between the cells,
and also to the interior of each cell.
The blood-vessels penetrate into the gland along with the
pancreatic duct, ramify in the lobes, and form a capillary network
FIG. 28. — Section of two fragments of human pancreas. Silver chromate method. (E. Muller.)
A, longitudinal section of excretory duct, lined with columnar epithelium ; m, lobular
ductules, giving off small diverticula between and into the alveolar cells. B, shows com-
mencement of ductules in alveolar cells (higher magnification).
round the lobules and the alveoli with highly uneven meshes,
some being so wide that many parts of the alveoli are scantily
irrigated with blood.
The pancreas contains nerve fibres, both medullated and
non-medullated, which unite with the sympathetic ganglia and
the isolated ganglion cells. On staining with Golgi's method
the fine nerve-fibrils can be followed into the alveoli. In some
n EXTERNAL DIGESTIVE SECEETIONS 89
carnivora, e.g. cat, numerous corpuscles of Pacini are seen in the
pancreas.
VII. The pancreatic, like the salivary, secretion is under the
control of the nervous system, for it begins a few minutes after
the food has entered the stomach, which must be due to a nervous
reflex transmitted from the afferent nerves of the stomach to the
efferent secretory nerves of the pancreas. Experiment shows that
these afferent nerves are stimulated by the hydrochloric and other
acids directly introduced into the stomach, which after a few
moments produce a copious pancreatic secretion. If the exciting
action of these acids is abolished, by neutralising them with the
introduction of alkaline fluids, the secretion is considerably
diminished or suspended (Pawlow). The same excitatory effect
is obtained when neutral fats are introduced into the stomach ;
but it is probable that these excite pancreatic secretion by acting
on the afferent nerves of the duodenal mucosa ; and also because
part of the neutral fats that enter the stomach are split into
fatty acids by the lipolytic enzyme of the gastric juice (Volhard).
These facts suggest that under normal conditions the secretion
of the pancreas is connected with the introduction of acid foods
and fluids, particularly the hydrochloric acid of the gastric juice,
which reflexly excites the secretory nerves of the pancreas. Direct
observations support this theory, and show that when gastric
secretion increases, the pancreatic secretion increases also.
Subcutaneous injection of atropine diminishes the secretion of
pancreatic juice, but does not suspend it, as in the case of saliva.
Injection of pilocarpine and physostigmine produce a contrary
effect to atropine (Gottlieb). Pilocarpine, however, does not
directly excite pancreatic secretion, but it excites a profuse gastric
secretion. The gastric juice, in its turn, on passing into the
duodenum, is able, secondarily, to determine the pancreatic
secretion. This is proved by Launoy's observation (1904) that, if
the stomach be tied at the pylorus, there is no longer any secretion
from the pancreas after pilocarpine injection, or, at most, only a
few drops of a very dense secretion.
Heidenhain showed that electrical excitation of the medulla
oblongata or cervical cord provoked pancreatic secretion if this
had been suspended, and accelerated it if the gland were already
functioning. Separation of the bulb from the cord by a transverse
section did not, however, arrest the secretion, showing that other
inferior centres besides that in the bulb affected the functions of
the pancreas.
Besides a centre for secretory nerves, the bulb appears also to
contain a centre for inhibition of secretion, since, on exciting the
central end of the vagus, the pancreatic secretion is arrested
(Bernstein). This effect is probably due to a reflex vaso-con-
strictor action, by which the blood-supply to the gland is much
90 PHYSIOLOGY CHAP.
diminished. The same result is obtained on stimulating other
sensory nerves, so as to excite nausea or vomiting.
Pawlow's subsequent work on dogs established beyond a doubt
that the secretory nerves of the pancreas run in the vagus. If in
a dog one vagus be divided in the cervical region, and the bulb
separated from the cord after 3 to 4 days by incision, artificial
respiration being given, and a pancreatic fistula established,
any stimulation of the peripheral end of the vagus by strong or
weak induced currents produces pancreatic secretion. Previous
researches carried out without these precautions had always led
to a negative result, owing to the great sensibility of the gland to
all influences capable of altering its blood-supply.
The vagus is not, however, the only nerve which contains
secretory fibres to the pancreas. According to Kudrewetzsky,
the splanchnic also supplies some, although their secretory action
is much less developed than that of the vagus.
A recent theory of Bayliss and Starling as to the mechanism
of secretion, whether of the pancreas or of other glands in the
digestive tube, has been very generally accepted.
According to these authors there is, besides the nervous con-
trol which is able in itself to excite pancreatic secretion, another
secretory mechanism, which acts independently of the nervous
system. This consists in an internal secretion by the mucous
membrane of the duodenum, of a special substance (secretin}
which, on entering the circulation, travels with the blood to the
pancreatic cells, exciting them directly and causing secretion.
Their theory rests particularly upon the fact that, on macerating
the mucous membrane of the intestine (especially of the duodenum
and adjacent parts) in a solution of hydrochloric acid, a solution
is obtained on filtering, which, when injected into the veins,
produces a profuse pancreatic secretion.
This fact has been controlled by many, and invariably con-
firmed ; but it does not seem to us to justify the theory that has
been based upon it. To say that secretin thus artificially prepared
is able to excite secretion in the pancreas and many other glands
does not mean that it is elaborated and circulated under normal
conditions of the duodenum. We know from an observation of
U. Lombroso (1903) that such is not really the case. In dogs
with a Pawlow's pancreatic fistula the secretion diminishes, and
ceases entirely after some days, if the papilla of the duct be
destroyed, even if the secretory ducts are still open.
The same occurs if, instead of establishing a pancreatic fistula
by Pawlow's method, it is prepared in Cl. Bernard's way, which
does not respect the integrity of the duct or the papilla. Why,
in all these cases, if the secretory mechanism of the pancreas
consisted (as on the hormone theory of Bayliss and Starling) in
the production of secretin during the passage of the gastric
ii EXTERNAL DIGESTIVE SECRETIONS 91
contents into the duodenum, should the pancreatic secretion
decline and cease ? Since the duodenum continues to receive
uniform .quantities of gastric juice, a corresponding amount of
secretin should be elaborated to carry on pancreatic secretion.
Popielski (1905-7) and his pupils have recently published a
series of experiments and conclusions which completely refute the
secretin theory. Popielski states that the substance extracted
after the maceration of the duodenal mucosa with hydrochloric
acid is not specific, but may, on the contrary, be obtained by
simple hydrolysis, from any glandular, muscular, or even nervous
tissue. Popielski further points out that no appreciable altera-.
tion of blood pressure can be observed on introducing hydrochloric
acid into the stomach to produce an abundant pancreatic secretion ;
whereas the so-called secretin has no sooner been injected (even
in small doses, with which much less secretion is obtained) than
a marked diminution of blood pressure occurs. According to
Popielski, this proves that the substance in question acts as a
vaso-dilatator.
But the following is the most cogent of Popielski's arguments.
On repeating the injections of secretin many times in equal doses,
he observed a conspicuous secretion after the first dose, less after
the second, less still after the third, till the substance rapidly
became ineffective. Now, the introduction of acid into the duo-
denum, however often repeated, invariably excites pancreatic
secretion proportional to the quantity of acid introduced. The
body evidently reacts to the introduction of secretin by forming
an anti-body capable of fixing it and annulling its action ; this
suggests that it is not a substance normally developed in the
body, but is an artificial extraneous product.
The pancreatic, unlike the salivary, secretion ceases when
pressure in the excretory duct reaches the maximum of 21 mm.Hg,
which is far below that at which the arterial blood circulates in
the gland (Pawlow). During secretion there is, as in the salivary
glands, an acceleration of local circulation, which Kiihne and Lea
observed directly under the microscope, in living rabbits. The
capillaries, which are too narrow to permit the passage of more
than a single erythrocyte, dilate during activity so as to allow of
more corpuscles passing simultaneously. The pulsation or trans-
mission of the blood-wave is visible in both the capillaries and
the small veins. These are phenomena of active vaso-dilatation,
from physiological excitation of the vaso-dilator nerves by paths
which are quite unknown to us.
Pancreatic secretion appears to be continuous in herbivora,
whose gastro-intestinal tube is never empty of food, and inter-
mittent in carnivora, which have a shorter digestive tube and
intermittent digestive processes. Colin observed in calves that
the secretion is continuous, but that it ebbs and flows in relation
92
PHYSIOLOGY
CHAP.
BF^aj
fe>
to the degree of digestive gastro-intestinal activity. According
to the observations of Heidenhain and his school, the secretion
ceases in fasting dogs, and
~A.^,2^fe:.r^J^fe:V^9fiAlM^> recommences during di-
gestion, continuing with
fairly regular fluctuations
throughout the process.
The rate of secretion
reaches its height in the
first 3 hours of digestion,
then slowly diminishes, to
rise again to a second maxi-
mum between the third and
seventh hours, after which
it falls rapidly to the mini-
mum. The interpretation
FIG. 20. — Pancreas of dog with permanent fistula, „ , . . . . , \.
showing changes in the alveolar cells owing to Ot thlS Will DC dlSCUSSCd
paralytic secretion. Alcohol - carmine method. .-.10.,,T,V1C>T,0
(Heidenhain.) ei&ew^nere.
In dogs, too, pancreatic
secretion may become continuous if the state of the gland is
altered. In this case (which recalls the paralytic secretion of the
salivary glands) the juice secreted is fluid and highly similar to
an ordinary transudate. The alveoli of the gland are reduced ;
the secretory cells have
lost the inner zone and
only keep the outer, so
that their whole contents
stain with carmine (Fig.
29). This change is an
exaggeration of what
occurs in the gland in
normal digestion.
According to Heiden-
hain's histological studies
of the pancreas, by the
alcohol-haernatoxylin and
carmine method, in the
first period of digestion
(which extends to 6-10
hours after the meal) the
outer, staining zone of T
°. . FIG. 30. — Dogs pancreas, excised during first period of
Secretory Cells IS enlarged digestion. Alcohol-carmine method. (Heideuhain.)
in dogs; the inner, granular
zone almost entirely disappears, so that the glandular alveoli
seem as a whole to be diminished in diameter. The alveoli
never show uniform changes, some being more, others less,
modified by the secretory process (Fig. 30).
EXTERNAL DIGESTIVE SECRETIONS
93
In the second digestive period (which includes the interval
between 10 and 20 hours after the meal) the alveoli increase in
bulk by a marked enlargement of the secretory cells. Their
FIG. 31. — Dog's pancreas, excised during second period of digestion.
Alcohol-carmine method. (Heidenhain.)
inner zone is much enlarged, while the outer is more reduced
than it was during fasting ; their nuclei are no longer round, but
flat and angular (Fig. 31). From all this Heidenhain concludes
that the inner zone of cells is consumed or dissolved during the
FIG. 32.— Two alveoli from pancreas of living rabbit, in state of rest and of secretory activity.
(Kiilme and Sheridan Lea.) A, resting state ; B, after secretion.
first stage of digestion, and regenerated at the expense of the
outer zone in the second, as if the one were transformed into
the other.
The later researches of Kiihne and Lea, obtained by direct
observations on live rabbits, have corrected Heidenhain's observa-
tions in accordance with the earlier doctrine of Johannes Mliller.
94 PHYSIOLOGY CHAP.
At the commencement of secretion, the cells of the tubular alveoli
undergo gradual changes which become very conspicuous. As is
partly shown in Fig. 32, the cells shrink in consequence of
secretion. The polyhedral cells become rounder ; the outlines of
the cells, which in the resting state are to a large extent invisible,
are well marked after secretion, with a double contour; the
granules of the outer zone move towards the lumen of the duct,
become smaller, less shining, and gradually disappear altogether.
It is therefore the secretory matter elaborated into granules by
the metabolic activity of the cells which dissolves and passes into
the secretion, and not the protoplasmic substance of the inner
zone of cells.
In spite of much research little is known precisely as to
the significance of the granules pointed out by Claude Bernard
and commonly known as zymogen granules, or their relation with
the functional phases of the gland. Kolliker, Henle, v. Frey, and
others who observed them before Bernard, regarded them simply
as fat - granules, owing perhaps to their round and refracting
surface.
If fragments of the pancreas are dissociated and pounded up
in a drop of serum, the granules are set free, and float for a long
while in the fluid before they dissolve. On adding acetic acid
they dissolve instantly, while in a solution of potash they first
swell and then dissolve slowly. Heidenhain, who (as we have
seen) observed variations in the number and arrangement of the
granules during the various stages of digestion, suggested that
they might consist of masses of pro-ferment. This hypothesis
was accepted by many authors who gave them the name of
zymogen granules.
But while the participation of the granules in the pancreatic
secretion is beyond doubt, there are certain observations which forbid
us to accept without further demonstration that they represent
the zymogen, or the whole zymogenic content of the gland.
Liversedge, Laguesse and Debeyre observed that maceration of
the pancreas with solutions capable of dissolving the granules
(acetic acid or alkali) yields an extract that is completely inactive
to protein, even on the addition of kinase which ought to activate
it (see Vol. I. p. 30).
On the other hand, U. Lombroso observed that 10 to 12 days
after ligation of the ducts, the pancreas of the pigeon, which no
longer shows any granules under the microscope, still exhibits
well-preserved enzymatic properties (amylolytic activity).
VIII. Alkaline while living, the pancreas after death gives
an acid reaction, which is probably due to the development of
lactic acid, and of fatty acids.
Chemical analysis of pancreatic tissue shows the presence of
an albumin, several globulins, nuclein and nucleo-protein (Spitzer),
ii EXTEKNAL DIGESTIVE SECKETIONS 95
various nitrogenous compounds, inosite, lactic acid, neutral fats,
volatile fatty acids, uric acid, and mineral substances. The
composition of the human pancreas is according to Oidtnaann —
Water ....... 74'53 per cent
Organic Substances . . . , . 24-57 „
Inorganic Substances 0-75 „
The most important substances it contains (the chemical
nature of which is still wholly unknown) are the three or four
zymogens, which are readily converted into their respective
enzymes, on which the digestive properties of the pancreatic juice
depend.
The pancreatic secretion differs entirely in its physical
characters and composition according as it is collected in a
temporary fistula of Wirsung's duct, or from a permanent fistula.
In the first case it is stringy and syrupy, forming in the cold at
0° a gelatinous mass, from which a fluid serum separates out.
This gelatinous mass readily dissolves in dilute acids. Owing to
the amount of protein, the pancreatic juice thus obtained coagulates
on heating. The secretion from the permanent fistula is more
fluid, and contains a smaller amount of organic matters. Both
the one and the other juice have digestive properties, but we
must hold with Pawlow that it is only the secretion from a
successful permanent fistula that represents the normal secretion,
since the pancreas is highly sensitive to all the lesions inevitable
in making a temporary fistula.
The quantity of juice that escapes from a fistula in a given
time is very variable, and therefore very difficult to estimate.
Some hold that the human pancreas secretes 150 c.c. per diem.
This appears to us to be too low an estimate. Since Pawlow
obtained 300-350 c.c. of juice from a dog that weighed about
20 kgrm., it is probable that a man would secrete over 500 c.c.
per diem.
The actual reaction of the pancreatic juice, which is almost
neutral (Farkas), must be distinguished from the potential reaction,
which is, on the contrary, intensely alkaline, and equivalent in
the dog to 1/1 On NaOH. Pawlow has observed that the alka-
linity of the pancreatic juice is equivalent to the acidity of the
gastric juice, and therefore suffices to neutralise the acidity.
Normal pancreatic juice contains a large amount of protein.
According to Zawadsky that collected from a fistula in a woman
operated on for pancreatic tumour contained in 100 parts —
Solids 13-59 per cent
Total Organic Substances .... 13-25 „
Albumin 9-21 „
Ash . 0-34
96
PHYSIOLOGY
CHAP.
Its most important constituents are the enzymes or soluble
ferments. These are usually three ; the diastatic enzyme
(amylopsiri), the proteolytic enzyme (trypsiri), and the lipolytic
enzyme (steapsin), to which a fourth, on which depends the
capacity of the pancreatic juice to coagulate milk (chymosin)
should perhaps be added. Pancreatic juice further contains a
substance which is precipitated by acetic acid (Halliburton) ; this
may be mucin or nucleo-protein. Besides these, xanthine, leucine,
fats, soaps, and salts, more especially alkaline chlorides, alkaline and
earthy carbonates and phosphates, have also been found.
Pure trypsin is a protein of unknown composition which in the
free state is soluble in water and insoluble in alcohol and
anhydrous glycerol, in which, however, it dissolves if not quite
pure. When dissolved in water, the solution being acidulated
and boiled, it splits into albumin and peptone (Kiihne). This
may, however, be not a true cleavage but a separation, as the
albumin may be considered an impurity (Loewi). When dissolved
in sodium carbonate and heated to 50° C. its proteolytic activity
is destroyed after five minutes : in a neutral solution it is destroyed
at 45° 0. ; it is also destroyed by the hydrochloric acid of the
gastric juice. Its digestive activity for proteins is best developed
in the presence of a 1 per cent solution of sodium carbonate, at a
temperature of 40° C.
The formation of trypsin in the pancreas has been more
closely studied than that of any other enzyme. If from a dog
that has fasted for 24 hours a glycerol extract of half the
pancreas is made immediately after the death of the animal
(extract 1), and of the other half when it has been left 24 hours
in the air at a temperature of 40° C. (extract 2) — taking in both
cases one part by weight of the pancreas (ground up with
powdered glass) and ten of glycerol, adding to both extracts a
1*2 per cent soda solution — it is regularly found that the first
extract has little or no digestive action upon fibrin, while the
second extract has a marked action. This experiment shows
that the fresh pancreas contains little or no trypsin, but that it
does contain a substance that can be transformed into trypsin,
which Heidenhain termed trypsin -zymogen (also known as
trypsinogen or protrypsiri).
This zymogen is insoluble in water. Its conversion into
trypsin is arrested or greatly hindered by the addition of a 1-2
per cent soda solution. But if the glycerol extract containing
zymogen is dissolved in sodium carbonate (1-2 per cent), and
oxygen passed through it for ten minutes, it becomes strongly
active by conversion of the zymogen into the enzyme. Zymogen
dissolved in distilled water that has been previously boiled
remains inactive ; in unboiled distilled water it becomes active
owing to the contained oxygen. The same transformation occurs
ii EXTEENAL DIGESTIVE SECRETIONS 97
with platinum black, with dilute acetic acid, and according to
Kiihne with absolute alcohol also.
According to Heidenhain the amount of trypsinogen in the
gland diminishes gradually from the commencement of digestion,
reaching its minimum after 6-10 hours. It then begins to
increase again, and reaches its maximum 16 hours after the meal,
when it remains constant for about 30 hours.
The other enzymes secreted by the pancreas have not been
fully worked out.
Amylopsin or pancreatic diastase was discovered by Valentin
in 1844, and again by Bouchardat and Sandras in 1846. It has
an amylolytic or saccharifying action upon starch, similar to that
of the ptyalin secreted by the salivary glands, but is more vigorous
and rapid, since it is able to act on raw starch. It has been
assumed capable of transforming large quantities of maltose into
dextrose ; other authors (Rohmann) maintain that this effect
depends upon another special enzyme, to which the name of
glucase has been given.
According to Korowin, Zweifel, and Sonsino the diastatic
power of the pancreas begins to develop in the second month after
birth, and is absent in the new-born.
Little is known in regard to the zymogen of pancreatic diastase,
as assumed by Liversedge. According to Griitzner the amount of
diastase contained in the pancreas fluctuates during digestion like
the trypsin ; it is minimal in the sixth hour of digestion, and reaches
its maximum 14 hours after the meal, after which it decreases
slowly, though it is still higher than in the first digestive period.
Steapsin (lipase), the enzyme which emulsifies fats, and splits
them into glycerol and fatty acid, was discovered by Cl. Bernard
in 1846 ; its hydrolytic power was subsequently confirmed by
Nencki, who showed that acetic acid ester and the esters of the
aromatic series (salol, benzonaphthol) are decomposed by the same
enzyme. It has never been isolated, and is certainly the least
known of the pancreatic enzymes. It can be extracted from very
fresh glands by a watery solution of sodium carbonate (Paschutin).
It does not dissolve in glycerol ; is destroyed by alcohol and
acids; is not found in glands that are not perfectly fresh. It
probably exists in the foetal pancreas because the meconium
contains free fatty acids. The optimum of its activity in regard
to neutral fats is reached at 38° C. Its action, like that of all
other enzymes, is destroyed by boiling. It acts better in a neutral
than in an alkaline medium.
Nothing is known of the zymogen from which lipase arises.
According to Griitzner this enzyme increases slowly in the
pancreas from the sixth to the fortieth hour after a meal, reaching
its minimum (like the other pancreatic enzymes) at the 6th hour
of digestion.
VOL. II H
98 PHYSIOLOGY CHAP.
We shall deal in a later chapter with all that concerns the
nature of the different digestive processes effected by the pancreatic
enzymes, and the conditions which favour, moderate, or inhibit
them — the importance, in short, of the pancreatic secretion to the
utilisation of food-stuffs in general.
Besides the pancreatic juice obtained by a temporary or permanent
fistula of Wirsung's duct, the digestive activity of the pancreas is tested by
making an artificial extract of the organ. This is prepared by grinding up
the pancreas, after dissecting away the fat and connective tissue, and drying
it in a desiccator over sulphuric acid. The dried residue is then treated
with alcohol and ether to remove the remaining fat, and macerated with a
1 per cent solution of salicylic acid at 40° C. for 12 hours, 500 c.c. of this
solution being used for every 100 grins, dried pancreas. The mass^ is then
filtered and squeezed through muslin. The solid material is digested for
12 hours at 40° C. in 500 c.c. of a 2'5 per cent solution of sodium carbonate,
containing a few drops of an alcoholic solution of thymol to prevent putre-
faction. The filtrate is rendered alkaline with the same solution, and also
allowed to digest at 40° C. for 12 hours. Both from the solid material after
filtering from any undissolved residue, and from the solution, a very active
artificial pancreatic extract is obtained.
From these extracts trypsin can be prepared in a state of comparative
purity by Kiihne's method. The extracts are allowed to digest for about a
week, when all the proteoses will be transformed into peptones. They are
filtered, and ammonium sulphate added to the filtrate to saturation. A fine
precipitate results, which carries down all the trypsin. This is dissolved in
water and dialysed, to remove the greater part of the ammonium sulphate.
The remainder of the sulphuric acid is precipitated as barium sulphate by
barium carbonate, and the clear filtrate is precipitated with alcohol. The
amorphous precipitate thus found is collected on a filter.
IX. That the pancreas exerts an internal function in carbo-
hydrate metabolism was suspected long ago by clinicians (Frerichs,
Cantani, Seegen, Bouchardat, and others), since post-mortem
examination of many cases of human diabetes showed profound
and varied alterations of this organ. But as little was known at
that time about the internal functions of glands, and there was
then no suspicion of the existence of such a function in a gland
provided with an excretory duct, they attempted to explain the
diabetes as an indirect consequence of the altered external
function of the pancreas. This gave rise to the hypothesis (to
which we must refer, because it is still maintained by certain
authors) that the food -stuffs being ill -digested, owing to the
absence of the pancreatic enzymes, developed toxic substances
which, when reabsorbed, inhibited the normal carbohydrate
metabolism.
It was long before any experiments threw light upon this
subject. The first attempts at extirpating the pancreas (Conrad
Brunner, 1788 ; Cl. Bernard, 1855 ; Berard and Colin, 1857 ; Senn,
1880 ; Martinotti, 1880) either resulted in the death of the animal
in a short time, making it difficult to analyse the phenomena, or
were so incomplete that no disturbance resulted from them, so
n EXTEKNAL DIGESTIVE SECKETIONS 99
that the function of the gland appeared not to be indispensable in
the various processes of metabolism.
Nor did glycosuria appear in other experiments (on dogs, cats,
and rabbits) in which destruction of the pancreas was attempted
in situ by ligation and section of the ducts, or their injection with
extraneous substances, such as oil, paraffin, acids, etc. (Cl. Bernard,
Schiff, Pawlow, Arnozan, and Vaillard).
In 1889 von Mering and Minkowski successfully accomplished
the total excision of the pancreas in dogs, and stated that
immediately after the operation there appeared regularly, along
with grave disturbances of alimentary absorption, an intense
glycosuria which lasted until the death of the animal, 2-3 weeks
later. The complex of symptoms was very like that of severe
cases of human diabetes (wasting diabetes}, so much so that it
was known by the name of experimental diabetes.
The results of von Mering and Minkowski were at once
confirmed by many authorities (Hedon, Lepine, Capparelli, etc.).
Since this glycosuria was evidently not due to impeded flow of
pancreatic juice into the intestine (as in the case of the permanent
fistula of Wirsung's duct), it was easy to deduce that it depended
not on the defective action of the secretion in the intestine, but on
the suppression of some other function exerted by the pancreas.
This idea, however, was and still is combated by some authors on
the strength of the following experiments.
De Dominicis, who excised the pancreas in dogs, simultaneously
with von Mering and Minkowski, sustained emphatically that the
glycosuria was not a constant phenomenon, and not in any case
determined by the suppression of an internal pancreatic secretion.
Glycosuria and all the other phenomena by which it is usually
accompanied (pollakiuria, polyuria, polyphagia, azoturia, phospha-
turia, etc.) depend, according to De Dominicis, upon a reabsorption
of toxines formed by the putrefaction of alimentary substances
that are not digested owing to lack of pancreatic juice. He
observed that injection of faecal extract from depancreatised dogs
produces slight glycosuria (1894), while injection of the duodenal
contents of depancreatised dogs produces an intense and persistent
glycosuria (1908).
Pflliger (1905) long refused to admit that the glycosuria conse-
quent on excision of the pancreas was due to suppression of a true
internal function of this gland. In his opinion the operative act
excites the nerve plexuses which traverse or have their terminations
near the pancreas, and which reflexly affect the centres which he
terms didbetogenic, leading to increased formation of glucose on
the part of the liver. This theory of Pfltiger, already brought
forward in 1892 by the brothers Cavazzani, was contradicted by
the experimental results of Lustig, Kaufmann, Marassini, Zamboni,
who, on more or less completely excising the solar plexus, or
100 PHYSIOLOGY CHAP.
dividing the nerves to the pancreatic region, obtained no diabetes,
but at most a slight transitory glycosuria. Moreover, Minkowski,
He'don, Thiroloix, Sandineyer, U. Lombroso, showed that after the
extirpation of a large part of the pancreas (leaving only the
processus uncinatus freed from all its relations with the duodenum,
save the large vessels) there was no glycosuria in the majority of
cases, although the lesions involving the nervous system of the
region were practically identical with those consequent on com-
plete extirpation, so that it was no longer possible for the external
secretion to be poured out into the intestine.
Pfliiger denied the value of this experiment, affirming that
if one nerve filament were left intact it was able to act vicariously
for all the rest, so that the presence of the nerve plexus which
accompanies the respective vessels would explain the absence of
glycosuria.
Hedon, who had already investigated the neural hypothesis,
tried to answer this last objection by dividing the neuro- vascular
peduncle of the pancreatic segment left in the body. His results,
however, proved little, because glycosuria set in after resection
of the peduncle ; still he noted that it almost always increases
when the pancreatic segment is excised.
The subsequent results of U. Lombroso in Minkowski's
laboratory may be regarded as an experimentum crisis against the
neural theory.
In a dog in which the processus uncinatus was grafted under
the skin, and which merely showed traces of sugar in the urine
(less than 0'3 per cent), the neuro-vascular peduncle was cut a
month after the first operation. Slight glycosuria appeared, and
vanished after four days, leaving the animal in the initial state.
After twelve days, on extirpating the segment of the pancreas so
as to separate it completely not only from the duodenum but also
from the abdominal cavity, severe diabetes at once set in, and
persisted till death.
De Dominicis refused to admit that these experiments, like
those which proved that glycosuria does not appear after ligation
of the pancreatic ducts, had any conclusive value against his own
theory. He pointed out that after ligation of the ducts or
excision of that part of the pancreas which contains the ducts,
alimentary absorption was far better than after total extirpation
of the. pancreas. This, according to De Dominicis, showed that
the pancreatic secretion was able in some way to reach the in-
testine, either by ducts that remained open or by a new formation
of ducts.
With this is associated another question that has recently come
under discussion. Does or does not the pancreas influence food
absorption, when it is no longer pouring its secretion directly into
the intestine ?
ii EXTEENAL DIGESTIVE SECRETIONS 101
De Doininicis, and uiore recently Visentini and 0. Hess, reply
in the negative.
According to Hess the dog's pancreas often has more than
two ducts, hence the experiment of tying the two ducts is not
conclusive. According to Visentini the divided ducts can easily
recover their functions. But these authors neglect the fact
that alimentary absorption can also be beneficially affected by
the presence of a segment of the pancreas completely separated,
not only from the duodenum (Abelmann, Pflliger, Hedon, U.
Lombroso, Eosenberg), but from the abdominal cavity as well
(U. Lonibroso).
Abelmann, Minkowski, Pflliger, Eosenberg, supposed that
absorption in these last cases still depends upon the external
secretion, this being reabsorbed and carried by the circulation to
the liver or the intestinal glands, whence it is returned to the
intestine.
Lombroso opposes this doctrine. He shows that by infusing a
certain quantity of pancreatic secretion into the vein, the enzy-
matic property of the bile might be profoundly altered for some
considerable time, whereas such modification does not occur after
occlusion of the orifices into the pancreas. He therefore thinks it
probable that in such cases there is no reabsorption of the pan-
creatic secretion. He has recently demonstrated (1908) in the
laboratory of Minkowski (who previously supported the opposite
theory) that a segment of pancreas, grafted under the skin, so that
its secretion is freely poured out externally, does promote food
absorption. Fleckseder, in Vienna, simultaneously arrived at the
same results as Lombroso, and therefore supports his theory.
In view of these results it is no longer possible to put forward
alimentary absorption as a proof that the pancreas with occluded
ducts is capable of pouring the products of its external secretion
indirectly into the intestine. The internal function of the pancreas
must, therefore, be not solely the arrest of glycosuria, but also,
though indirectly, the promotion of food absorption. We shall
return to this subject in treating of the absorption of food.
The next question is whether this internal function of the
pancreas connotes a special secretory process or no. He"don holds
that it should be possible to prove the existence of an internal
secretory function of the pancreas, by the modification of experi-
mental diabetes with the introduction of glandular extracts into the
circulation, just as the thyreopriva syndrome can be modified by
administration of thyroid extracts.
Eesearch in this direction has yielded only doubtful or contra-
dictory conclusions. Capparelli (1891-92) obtained favourable
results in depancreatised dogs with injection of very fresh pan-
creatic pulp. Eecent observations of Ziilzer, Dohrn, and Maxer
(1908), on both human and experimental diabetes, had the same
102
PHYSIOLOGY
CHAP.
result. On the other hand, the conclusions of Hedon, Gley, Lepine,
and many others were negative. To us it seems too large an order
to assert that artificial injections of glandular pulp can replace a
physiological function which develops in a continuous and regular
manner, or to give a decisive value to negative results in such
questions.
A very ingenious experiment, which tells in favour of a true
internal secretion of the pancreas, is that of Forschbach (1908) with
the method of paraMosis. This consists in uniting two animals of
the same species and litter with a triple suture (cutaneous,
muscular, peritoneal). In the animals thus operated on, there is
an exchange of blood by the blood-vessels and lymphatics of the
two communicating abdominal cavities, and it has been shown
that many substances (iodine, sugars, alkali, etc.) injected into
one animal pass rapidly into the other.
On extirpating the pancreas from one of the two dogs in
parabiosis, pathological disturbances do not set in with the severity
described above : in some cases they are very slight, but become
aggravated as soon as the depancreatised dog is separated from
the other.
Biedl observed permanent glycosuria after ligation of the
thoracic duct, or when the whole of the lymph had been drawn off
externally, and found (with Offer, 1907) that this experimental
diabetes disappeared on injecting lymph, which suggests that the
internal secretion of the pancreas may be discharged by the
lymphatic system.
These observations render the hypothesis of an internal
secretion the most probable among the many that have been
proposed to explain the internal function of the pancreas.
X. Given the existence of an internal function of the pancreas,
and assuming it to be served by a special secretion, Laguesse,
Schafer, Opie, and others formulated a theory that has been widely
accepted. The two secretions of the pancreas, external and
internal, are held to be distinct functions of different cells, the
former being served exclusively by the alveoli, the second by the
islets of Langerhans.
The morphological arguments for this theory are, however,
inadequate, and too much a matter of controversy to be conclusive.
They rest on the well-known fact that the islets are provided
with numerous blood-vessels, and on the assertion (supported by
very few authors) that they are completely invested by a capsule of
connective tissue and contract no relations with the excretory
ducts.
If this could be proved, the insular theory would obviously
have a valid anatomical basis. Even so, however, the possibility
that the alveoli also contribute to the internal secretion would not
be excluded. Moreover, the fact that the islets contain numerous
ii EXTERNAL DIGESTIVE SECRETIONS 103
blood-vessels is no proof that they serve the internal secretion to
the exclusion of the alveoli. It is still conceivable that the
internal secretion of the pancreas may be discharged by the
lymph capillaries. Biedl's observations as previously quoted
support this hypothesis.
Morbid anatomy does, indeed, support the view that the
islets are the exclusive organs for the internal secretion of the
pancreas. Numerous observations (Hanseinann, Opie, Gutemann,
Karakascheff, Ssobolew, Herxheimer, Schmidt, Sauerbeck, Visentini,
Herzog, Reitmann, etc.) show that the pancreas may exhibit
different features in human diabetes. In some cases there is no
alteration either of alveolar or of insular tissue. But in the great
majority of cases the pancreas is profoundly and diffusely altered,
both in the alveoli and in the islets. It is rare for the
degeneration to involve alveolar tissue only, still more rare that
the changes should be confined to the islets.
The rare cases of diabetes with a healthy pancreas prove that
this disease is not necessarily pancreatic in origin ; which does not
alter the fact that the pancreas normally discharges an internal
secretion which affects carbohydrate metabolism.
The rare cases of diabetes in which either the islets alone
or the alveoli alone are modified, cannot be taken as a decisive
argument in favour of the theory which ascribes the internal
secretion of the pancreas exclusively to the islets (Laguesse) or to
the alveoli (Hansemann); at most they suggest the hypothesis
that both these tissues co-operate actively in the normal internal
secretion of the pancreas.
Experiments with the object of localising the external and
internal secretions of the pancreas in its two tissues have been
numerous.
Schultze and Ssobolew (1900) were the first who maintained
the insular theory of internal secretion, starting from the fact that
after ligation of the ducts or internal pancreatic lobes in the
rabbit, the islets were left unaltered, while the alveoli were
modified and disappeared, without causing any true diabetes.
The same fact had been described by Vassale ten years earlier,
but not with the intention of localising the internal secretion
in the islets : he merely sought to contradict Lewaschew, who
affirmed the unitary character of the two pancreatic tissues.
Mankowski and Lombroso failed to confirm the results of
Schultze and Ssobolew. They found that ligation of the ducts in
the rabbit produced alterations not merely in the alveoli but
also in the islets, which diminished in size and number.
Many other authors (Tiberti, Pende, Marassini, etc.) obtained
substantially the same results; some (Laguesse, Marassini),
however, argued from the greater resistance of islets as compared
with alveoli, that the absence of glycosuria must be referred to the
104
PHYSIOLOGY
CHAP.
survival of the islets, the internal secretion being served by the
islets only.
Louibroso objected that the necessary counterproof was
wanting. It is not known whether complete extirpation of the
pancreas (as far as possible) would
produce glycosuria in the rabbit.
It is known, indeed, that complete
ablation of the pancreas is not followed
by glycosuria in all animals. It is
absent in many granivorous birds
(pigeons), while it is seen in carnivora
(crows, falcons). Moreover, the effects
of total excision of an organ, and of
the slow and gradual suppression of
its function, may differ considerably.
Even in the dog, according to Hedon,
glycosuria may be absent or very slight
when a pancreas previously altered by
injection of paraffin into its ducts is
excised.
After tying or cutting the ducts,
and after transplanting a segment of
the pancreas in the dog, numerous
observers (Hedon, Moruet, Laguesse,
Ssobolew, De Dorninicis, Hansemann,
Lombroso) found that conspicuous
groups of alveoli or of islets might
survive in perfect preservation, even
for a long time after the operation.
It was only in grafts upon animals
which had rapidly perished, that both
alveoli and islets were found to be
degenerated. On these data Lombroso
founded his theory that islets and
alveoli both co-operate in the internal
G.^ 33.— section through the coats of secretion of the pancreas.
Zuntz and Mayer extended the
period of observation with dogs thus
operated on to 440 days, and obtained
the same results as Lombroso. Visen-
tini, on the contrary, out of 24 dogs
operated on by tying and cutting the two pancreatic ducts, found
in two of them (after 160 and 212 days, respectively, after the
operation) that the alveoli were not in the normal state, while the
islets, on the contrary, were well preserved. He omitted, however,
to notice the effect of excising the pancreas when thus altered, so
as to see how far it had been capable of functioning as an organ
the stomach. Diagrammatic. (Mall.)
TO, mucous membrane ; e, epithelium ;
d, orifice of gland duct ; mm, muscu-
laris mucosae ; sm, submucous coat ;
cm, circular muscular layer ; Im,
longitudinal muscular layer; s, ser-
ous coat.
ii EXTEENAL DIGESTIVE SECRETIONS 105
of internal secretion. Lombroso's observations indicate a constant
relation between the degree of glandular degeneration in cases
when a segment is grafted under the skin, and its function before
and after excision. The less the segment is altered, the better it
accomplishes its internal function, and the more acute are the
effects of extirpation.
All this evidence is at present too inconclusive to determine
whether the internal secretion of the pancreas is exclusively
confined to the islets of Langerhans, or if the alveoli also
contribute to it. This question must be left in abeyance for
future research.
XL The walls of the Stomach, in a vertical section, show four
coats or layers, known from without inwards as the serous,
muscular, submucous (or areolar) and mucous membranes
(Fig. 33).
The 'mucous membrane of the stomach, which alone concerns
us, is in two parts, the pyloric end, which is pale in colour,
with fewer longitudinal folds, and the
fundus, which is reddish, yellow, or brown,
with more frequent and irregular' folds
forming a network. Beside these coarse
folds (which are obliterated when the organ
is distended with food), a lens shows pro- _
., . P « i Fl«- 34.— Epithelium of surface
On the internal Surface Of the of stomach examined fresh.
stomach, with corresponding depressions of y magnil
polygonal shape, which become larger and
deeper near the pyloric orifice. These are the mouths of the
tubular glands with which the gastric nmcosa is beset.
Taken as a whole, the columnar epithelial cells which cover the
mucous membrane of the stomach (Fig. 34), may be regarded as a
secreting organ which is not, like the glands we have been
discussing, gathered into a small space, but is spread out over the
surface. The function of this secreting surface does not differ
specifically from that of the simple and compound mucous glands
found in the buccal cavity and along the mucous membrane of the
oesophagus. The columnar epithelial cells of the stomach are,
however, richer in albumin than the mucous cells of the sub-
maxillary gland, and behave very differently from them when
treated with acetic acid ; they do not become clouded, but are
clear and swollen. With mineral acids, and on hardening with
alcohol, the submaxillary cells scarcely cloud at all, while those of
the gastric epithelium become quite turbid (Heidenhain).
The appearance of the columnar epithelium differs to a marked
extent in the state of rest and of digestive activity. In the
latter, many of the cells become goblet-shaped, open to the out-
side, and half -empty, owing to escape of the mucin which is
elaborated from the mucinogen formed inside the cell.
Pio. 35. — (Left.) Pyloric gland, from a section of dog's stomach. (Ebstein.) TO, mouth ; n, neck,
tr, deep portion of a tubule cut transversely.
FIG. 36. — (Right.) Cardiac gland, from dog's stomach. Highly magnified. (Klein and Xoble
Smith.) d, duct and mouth of gland ; b, base or futulus of a tubnle. On the right is the
base of a tubule more highly magnified ; c, central cell ; p, parietal cell.
CHAP, ii EXTEKNAL DIGESTIVE SECEETIONS
107
The specific secretory organs of the stomach consist of two
kinds of glands, which differ both in the character of the cells that
line the duct and in the nature of their secretion.
Most of the glands at the pyloric end have a long neck, lined
with cells identical with those on the surface of the mucosa, and
a short body, which is nearly always made up of a number of
tubules, lined with an epithelium that is quite different from that
of the neck or excretory duct. It consists
of finely granulated columnar cells, which
are never goblet-shaped, and which react
specifically to various stains (Fig. 35). In
the glands of the fundus the duct is
narrower, the neck shorter, and the body
longer. But they differ from the pyloric
glands mainly in having two kinds of
secreting cells: those which Heidenhain
termed chief — the central or peptic cells,
and those he calls border — the parietal or
oxyntic cells. The first are similar to the
cells of the pyloric glands, the second are
larger, more irregular in form, darker when
hardened in alcohol, more easily stained
(Fig. 36). It was formerly supposed, in-
correctly, that the first kind of glands were
found exclusively in the pyloric region, the
second in the curvature and fundus. In
reality the former are more abundant in
the pyloric and the latter in the fundic
region (Stohr).
As we have seen for the salivary
glands, so in the gastric, the duct which
runs through the tubule is prolonged into
canaliculi between the cells, and forms a
basket-like capillary network round the
parietal cells (Fig. 37).
The stomach is richly supplied with
blood by numerous vessels from the caeliac
trunk, which form a plexus beneath the submucosa. Each tubule
is lined with a capillary network, from which the veins form again.
They are few in number, but are larger than the arteries, with a
stronger muscular coat than is usual in veins, and many valves
(Hochstetter).
The lymphatics of the stomach arise in a rete of lacunar spaces
that lie between the tubules of the gland and form a more ample
plexus in the submucosa, whence the efferent lymphatics emerge
to traverse the muscular coats and the lymph nodules situated
along the two gastric curvatures.
FIG. 37.— Secreting duct of gastric
gland. Golgi's silver chromate
method. (E. Miiller..) Thecells
are not represented, but the
lumen extending into the net-
work surrounding the parietal
cells is deeply stained.
108 PHYSIOLOGY CHAP.
The nerves to the stomach consist of the terminal gastric
branches of the vagus, and the sympathetic fibres of the solar
plexus. Both are almost invariably composed of non-medullated
fibres. Numerous small ganglia (according to Remak) form
plexuses with these nerve fibres, either between the layers of the
muscular coat or in the submucosa. From these plexuses, nerve
fibres run through the muscular tissue, or the glandular tissue of
the mucous membrane.
XII. Until recently the direct influence of the nervous system
on gastric secretion was regarded as doubtful. The results of
experiments were either negative or less obvious than for the
salivary secretion. Recent experiments have fully elucidated this
point.
The flushing of the gastric mucosa owing to active vascular
dilatation during digestion, the increased rate of circulation which
causes bright red blood to flow through the veins that differs
little from that in the arteries (Claude Bernard), are phenomena
perfectly analogous to those observed during salivary secretion.
They show the existence of vasomotor nerves to the stomach, and
justify the conjecture that special secretory nerves control the
gastric, like the salivary, secretion.
A stronger argument for the direct nervous control of gastric
secretion lies in the fact that in fasting animals with a gastric
fistula, the mere sight or smell of some favourite food causes a
flow of gastric juice through the fistula (Bidder and Schmidt,
1842 ; Schiff, 1865). This is not due to deglutition of saliva,
which might excite the gastric mucous membrane, because the
same thing is seen when the ducts of the salivary glands or the
oesophagus are occluded in the dog. The secretion "psychically
excited " by sight or smell does not begin immediately, but only
after some (5-15) minutes, and persists for a long time after
cessation of the stimulus (Sanotzky, 1892).
Greater interest attaches to Eichet's observations (1878) on a
girl who had stricture of the oesophagus and was fed through a
gastric fistula. Each time she was made to chew or taste a highly
sapid substance (sugar, lemon juice, etc.) while fasting, a con-
siderable quantity of juice flowed from the fistula. This was
undoubtedly a reflex secretion, but it was uncertain whether the
reflex directly promoted the secretion, or if, by dilating the vessels
of the stomach, and contracting its muscular coat, it determined
the secretory phenomenon indirectly.
Pawlow and Mme. Schumowa-Simanowskaia (1889) made a
series of striking experiments in order to decide this question and
clear up these phenomena of the innervation of the gastric glands.
They established the usual gastric fistula on dogs, and in a
subsequent operation divided the oesophagus half-way up the neck,
and sutured the two ends to the lips of the cutaneous wound, so
ii EXTERNAL DIGESTIVE SECRETIONS 109
that when the animal fed the alimentary bolus dropped out
through the oesophageal fistula. For food to reach the stomach it
was necessary to introduce it either through the lower orifice of
the oesophageal fistula or through the gastric fistula.
When an animal thus prepared was made to masticate and
swallow food that dropped out again through the oesophageal
fistula (sham or imaginary feeding), a marked secretion of gastric
juice (psychical secretion} was invariably noted 5-6 minutes later.
On section of the vagi (the right below the point at which the
cardiac branches and the inferior laryngeal are given off, and the
left at the neck) this reflex secretion ceased entirely. On exciting
the peripheral trunk of the left vagus with two induction shocks
per sec. the flow through the fistula reappeared.
These results, which were constant under the given con-
ditions, contradicted the previous negative results of vagus
.excitation obtained under other experimental conditions by many
physiologists, Heidenhain included. They prove beyond doubt
that the centrifugal nerves that regulate the gastric secretion are
contained in the trunk of the vagus.
Von Mering (1899) showed that atropine and pilocarpine pro-
duce similar effects on gastric secretion to those which Heidenhain
obtained on salivary secretion : the former diminishes or suspends
secretion of gastric juice, the latter increases it even fourfold.
These effects can only be explained by admitting that atropine
has a paralysing, and pilocarpine an exciting, action on the
secretory fibres contained in the vagus.
Other facts, however, show that the gastric secretion does not
depend exclusively upon the secretory fibres of the vagus, since
the stomach is capable of sufficiently digesting the alimentary
substances introduced into it, even when the vagi have been
divided. This suggests that other secretory fibres, spinal or
sympathetic in origin, influence the gastric glands: but there are
at present no experimental proofs of this conjecture. Experiments
made with this object (section of splanchnic, excision of caeliac
plexus) have given negative results. Heidenhain assumed that
the digestive capacity of the stomach persists after division of the
centres of all cranial and spinal nerves to the stomach. It is
probable (although it has not been experimentally demonstrated)
that the gangliar plexuses in the walls of the stomach represent a
system capable of special reflex activation of secretion.
The stimuli that normally determine gastric secretion by reflex
paths are the food -stuffs, which excite the nerves of taste and
other centripetal nerves to the mucous membrane of the mouth,
pharynx, oesophagus and stomach. The fine experiments of
Pawlow and his collaborators (1889-97) have established as an
indispensable condition of the production of a flow of gastric juice
by the aliments introduced through the mouth, that the animal
110 PHYSIOLOGY CHAP.
shall have appetite for the food offered it. Mechanical or non-
sapid stimuli applied to these sensory surfaces are not effective in
promoting gastric secretion to any appreciable extent (contrary to
what was formerly held). When, on the other hand, sham feeding
has been carried on for only five minutes with the oesophageal and
gastric fistulae, the secretion of gastric juice lasts 23 hours or even
longer. This can only be explained by assuming that the excita-
tion of the taste centre persists for the whole of this time.
Section of the vagi, by which the psychical influence is trans-
mitted to the gastric glands, in fact suffices at once to arrest the
secretion.
Cohnheim and Soetbeer (1903) showed that in new-born
puppies, which had a gastric fistula with divided oesophagus
(Pawlow's method), the act of sucking produced an abundant
psychical secretion of gastric juice. Psychical secretion, therefore,
appears to be a congenital reflex as hereditary in these animals •
as that of sucking, and not acquired by individual education and
force of habit.
It is very probable that the mechanical acts of mastication and
suction may not in themselves have any influence upon the secretory
work of the stomach. This agrees with Hornborg's observations
(1904), showing that when a bit of gutta-percha, i.e. an indifferent
substance, was masticated there was no gastric secretion, while
mastication of sapid substances is always followed by secretion, or
by an obvious increase of the flow.
According to Schiile (1901) pure psychical secretion in Pawlow's
sense is seldom manifested in man. The acid secretion of the
gastric glands is excited by the action of a purely chemical reflex,
due to the alimentary substances which come into contact with
the gastric mucosa. He further remarks that in man the act of
mastication in and by itself, independent of psychical associations
(taste, smell), must come into play in determining the secretion
of gastric juice, as well as the direct contact of the food stuffs.
In order to study the process by which gastric secretion occurs
when food is present in the stomach, Heidenhain, in a bold
surgical operation, separated a portion of the fundus of the dog's
stomach, and reduced it to a closed sac or pouch communicating
with a fistulous opening to the outside, after which he restored con-
tinuity to the remainder of the viscus by stitches. In this operation
the branches of the vagus, by which the taste centre transmitted
the secretory stimulus to the gastric glands, were divided. There
was no secretion in the isolated sac of the fundus during the
mastication and deglutition of meat. It only begins 15-30 minutes
after ingestion, and lasts a longer or shorter time, according to
the nature and amount of the food ingested, i.e. 13 to 14
hours after a moderate meal, 16 to 20 hours after a heavy one.
If instead of meat the animal is given some very indigestible food,
ii EXTERNAL DIGESTIVE SECRETIONS 111
e.g. ligamentum nuchae coarsely cut up, there is no secretion in
the sac. This only appears when, after such a meal, the animal
is given drink, but in this case it lasts a very short time, from
1£ to 4 hours at most.
This fact was confirmed by Sanotzsky (1892), who held, like
Heidenhain, that it depended on a reflex excitation (other than
that of the secretory fibres of the vagus), or on a direct excitation
of the secretory gland cells, due to the action of the digestive
products absorbed by the walls of the stomach.
Khizhin (1895) held, on the contrary, that the secretion was
due to chemical excitation of the centripetal nerve-endings of the
gastric mucosa by certain special foods, previous to their absorption.
Direct mechanical stimulation of the mucous membrane also
produces secretion, but to a negligible extent.
There can be no question, as to the gastric secretion being, at
least in the first instance, determined by nervous stimuli. On the
other hand, the influence on which the continuation of the
secretion depends is still debateable. According to Pawlow, it is
a chemical action on the peripheral nerve-endings, of the digestive
products of the proteins. He observed a profuse secretion when
peptones, extract of meat, etc., were introduced into the stomach,
without the animal being aware of the same.
But after Bayliss and Starling published their hormone theory
(mentioned above in treating of pancreatic secretion), which
obtained a large following, experiments were set going to see
whether the same might not hold good for gastric secretion also.
Edkins (1905) demonstrated that it was possible to extract a
substance from the pyloric mucosa which produced a secretion of
gastric juice when injected into the circulation, while extract of
the mucosa of the fundus had, on the contrary, no effect.
This substance pre-exists in an inactive state, and becomes
active on adding acids, or on boiling (which proves it not to be an
enzyme).
Frouin (1905) noted that the subcutaneous injection of 40 c.c.
of gastric juice considerably increased the gastric secretion in dogs
with isolated stomachs, from which he deduced the existence in
the gastric juice of substances that have the property of increasing
the secretory activity of the gastric mucous membrane.
Without questioning the data cited by these authors, it seems
a little premature to use them (with the followers of Bayliss and
Starling) as arguments in favour of the hormone theory, which
has been shown, in speaking of secretin and the pancreatic secretion,
to be ill-founded.
The amount of juice secreted by the small stomach always bears
the same ratio (taking into account the extent of the secreting
surface) to the amount secreted by the large stomach, in sham
feeding. The degree of acidity, too, is much the same, but the
112 PHYSIOLOGY CHAP.
digestive power is decidedly weaker. This digestive power de-
creases from the first to second, or first to seventh hours, then
rises again and reaches its maximum at the fifth, or according to
other experiments, the. eighth hour.
Pawlow and his co-workers have recently succeeded in isolating
a closed pouch or cul de sac from the stomach, without injuring
the vagus fibres that control secretion (infra, page 114). From
the animals thus operated on, they have collected important data
relative to the influence upon the secretion of the blind sac
of certain alimentary substances introduced into the stomach. In
order to exclude reflexes by the secretory fibres of the vagus
excited from the surface of the mouth, pharynx, and oesophagus,
the food is introduced into the stomach by the sound. The results
may be summarised as follows : —
(a) Water, O'l-O'o per cent solutions of hydrochloric acid,
O'01-l per cent salt solutions, introduced into the' stomach in
amounts of 100-150 c.c., produce only a very weak secretion of
juice in the blind sac.
(6) Water, 0'5 per cent salt solution, 10 per cent solutions of
cane-sugar or starch, in quantities of 500 c.c., produce a stronger
secretion, which commences 13 to 29 minutes later, and lasts some
60 to 135 minutes.
(c) These substances do not affect the secretion of the blind
sac in themselves, but in virtue of the water in which they are
dissolved. In fact, if plain distilled water is injected into the
stomach, a secretion of equal quantity and duration is evoked.
(d) When, on the contrary, peptone is introduced into the
stomach by the sound (this being, as we shall see, the principal
product of the digestion of proteins by the gastric juice), there is,
after about 13 minutes on an average, an abundant secretion in
the pouch which lasts for some 3 hours.
(e) Neither ov-albumin nor proteoses produce a similar effect.
They only cause a weak secretion for a short time, which may be
due to the amount of water in which they are dissolved. We may
conclude that peptone is a specific stimulus for the secretory
elements of the stomach, probably because it is capable of exciting
the centripetal nerve-endings of the mucous membrane, which
determine the secretion reflexly by the centrifugal paths of the
vagus, and possibly also by way of the sympathetic.
(/) Other observations show that after the secretion from the
sac has been started by the stimulus of peptone, it increases
considerably when egg-albumin is introduced into the stomach,
though this by itself is ineffective.
(g) The gastric secretion excited by the presence of food in the
stomach reaches its maximum in the first and second hours (after
ingestion of milk only in the third hour). After that it gradually
diminishes, and then ceases entirely. For any given kind of
ii EXTEBKAL DIGESTIVE SECKETIONS 113
food the absolute amount of juice secreted increases with the
amount ingested. For different kinds in equal quantities, the
absolute amount of secretion varies ; it is greater for meat than
for bread, for bread than for milk (Khizhin and Lobassoff, 1897).
(h) The introduction of carbohydrates excites no secretion of
gastric juice (Barbera, 1898) ; that of fats may cause its diminution
or arrest if it is already present (Khizhin, 1895 ; Lobassoff, 1897).
This inhibitory action of gastric secretion by fats has been
carefully studied by Pawlow's pupils. Their observations show
that not only is the total quantity of gastric juice diminished, but
the enzymic activity of the secretion is also depressed. Thus,
e.g., on administering 400 grms. of flesh to a dog provided with
Pawlow's miniature stomach, about 40 c.c. of secretion was obtained
in the first four hours, with a peptic digestive power (measured by
Mett's method in mm.) equal to 5 '00. On adding 75 c.c. olive oil
to the 400 grms. flesh, a secretion of only 18 c.c. was obtained,
with a digestive power lower by 3 mm.
The inhibitory action of fats is shown particularly in the first
period of digestion (in which the influence of psychical factors is
specially felt). Sham feeding in a dog operated on by Pawlow's
method, when the large stomach contains oil, or has been subjected
for some time to the action of oil, produces a secretion much less
in quantity and activity than the same sham feeding when the
stomach has not been acted on by fat.
These observations have an important practical significance,
since they justify the long-established use of fats in therapeutics,
for the cure of gastric ulcers, or of gastric hyper-secretion which
predisposes to ulcers.
(i) Alcohol in moderate doses excites, in excessive doses arrests
gastric secretion (Bernard, Lussana, Albertoni). Many observa-
tions have been made upon the use of alcoholic beverages (wine,
beer, liqueurs) in relation to the gastric secretion. Many authors
admit that these excite gastric secretion. But it is still unknown
whether this is by simple psychical reflexes (sight, smell, agreeable
taste) or by direct excitation of the mucous membrane.
Frouin and Pekelharing showed that on administering alcoholic
solutions per rectum the increase in secretion was to be attributed
to the absorption of alcohol in the blood, by which the cells of the
gastric glands are excited immediately, or mediately by the nerves,
to an extent corresponding with the amount of alcohol absorbed.
(k) With an empty stomach there is normally no gastric
secretion, provided there are no central taste stimuli to provoke it
reflexly. On opening the tap of the cannula of a gastric fistula in
a dog that has fasted for over twenty-four hours, only mucus as a
rule flows out, which usually gives an acid, more rarely a neutral
or alkaline reaction. In a woman with oesophageal occlusion due
to cancer of the cardia, operated on by gastric fistula by Postempski,
VOL. n I
114
PHYSIOLOGY
CHAP.
Bocci constantly observed an acid reaction from the gastric niucosa,
twelve hours after the last meal. We must not assume from this
that gastric secretion is continuous. When gastric juice, with
all its chemical and physiological characters, flows from gastric
fistulae in animals or man, with a perfectly empty stomach, under
perfect physiological conditions, it can easily be shown that this
apparently spontaneous secretion is aroused by psychical taste-
suggestions (Pawlow).
In order to study the course of gastric secretion, i.e. its quantitative and
qualitative modifications during digestion, it is convenient to employ
FIG. 38. — A, stomach of dog previous to Pawlow's operation, showing direction of principal
nerves. B, stomach after the operation, which has divided it into two, the large (K), and the
miniature stomach or blind sac (S), which is sutured to the abdominal walls (AA), and com-
municates with the exterior by means of a fistula. S, serous coat; muse., muscular coat;
muc., mucous membrane of wall of stomach operated on.
Pawlow's " miniature stomach " or pouch, which served for most of the
experiments we have been discussing. It is prepared as follows : —
The first incision A, B (Fig. 38, A), which begins in the fundus of the
stomach, 2 cm. from its junction with the pyloric portion, is carried in the
longitudinal direction through all the coats of the anterior and the posterior
wall for 10-12 cm. along the great curvature. A triangular flap C, C is thus
formed. A second incision is made exactly at the base of this flap, but only
through the mucous membrane. The serous and muscular coats are left intact,
and pass from the main stomach into the flap, while the mucosa is completely
separated from it. The edges of the mucous membrane of both stomach and
flap are detached from the submucous tissue for l-l£ cm. from the wall of
the stomach, and 2-2£ cm. from the wall of the flap. The posterior and
anterior margins of the mucous membrane of the stomach are then brought
together and sutured in a straight line from cardia to pylorus. The flap
is converted into a cup. Lastly, the margins of the incision, in the walls of
stomach and flap are stitched together. The cavity of the stomach is thus
restored, and the flap remains as a pouch, or small appendicular stomach
ii EXTEKNAL DIGESTIVE SECEETIONS 115
(Fig. 38, B), which is united to the main stomach by the two outer walls.
The two cavities lined with mucous membrane are completely separated by
a double septum consisting of the sutured mucous coat of the stomach and
that of the cup-shaped flap. The opening of the pouch is stitched to the
abdominal wall (A, A).
XIII. The chemical composition of the gastric juice must be
studied before discussing the process by which it' is formed.
The gastric juice obtained by C. Schmidt from a healthy
woman with a gastric fistula, after the ingestion of peas and a
little water, was found to be a clear thin fluid, much less acid
than that of the dog, with specific gravity of 1-0022-1-0024. It
became slightly cloudy on boiling, and left a solid residue of
about 2 per cent.
The gastric juice obtained by Pawlow and his co-workers and
pupils from the dog by the above method of sham feeding is
certainly purer, as well as that obtained from the fundus sac by
Pawlow's method, which preserves the integrity of the vagus
fibres.
This pure secretion, which is free of all alimentary residues, is
as clear as water, acid, with no extraneous taste, specific gravity
1-0030-1-0059. It turns the plane of polarisation to the left
(from 0'70° to 0'73° in a layer of 20 cm.). On evaporation it leaves
a solid residue of 0-29-0-60 per cent; 0'10-0-17 per cent ash on
combustion. It constantly contains a little protein, but no
peptone, leucine, nor tyrosine. On lowering the temperature it
becomes cloudy, and forms three layers: the top one clear, the
middle turbid, the lower consisting of a deposit of homogeneous,
highly-refracting granules.
According to the chemical analysis made by Mme. Schumowa-
Simanowskaia of the secretion obtained from the dog by sham
feeding, its composition is as follows : —
Acid . . . .
Chlorine
Dry residues
Ash
Substances coagulated by alcohol
Substances coagulated by boiling
Substances precipitated at 0° C. .
Phosphoric acid . . . ;
0-46-0-56 per cent.
0-49-0-62
0-43-0-60
0-09-0-16
0-14-0-19
0-13-0-18
0-011-0-003
0-004
As we shall see elsewhere, the digestive activity of the gastric
juice is due to the hydrochloric acid and the enzymes which it
contains, these being the specific secretory products of the gland
cells. The quantitative variations of these products, and the
process and seat of their formation are as follows : —
(a) The acidity of the gastric juice, owing to the constant
presence of a free acid, is well established for all vertebrates.
Prout (1824) was the first who suggested that this free acid was
116 PHYSIOLOGY CHAP.
hydrochloric acid; but C. Schmidt (1852) first proved it, and
showed that the gastric juice of the dog and pig contained chlorine
in excess of what was required to combine all the inorganic bases
obtained by calcination of the solid residues of the gastric juice.
This fact shows that a considerable part of the chlorine is
combined with hydrogen in the form of free hydrochloric acid.
Other acids can be detected in the gastric juice, lactic acid in
particular, which is also thought by many to be a secretory
product of the gastric glands. Everything, however, points to the
probability that lactic acid is a decomposition product of carbo-
hydrates produced by special bacteria, that are able to live inside
the stomach. The same applies to the butyric acid that has
occasionally been found in the gastric juice.
The amount of hydrochloric acid in the gastric juice varies
considerably in different animals. It is much more abundant in
dogs ( = 0'46-0*5S per cent) than in man ( = 0'1*7 per cent on an
average). But the exact determination of the amount of hydro-
chloric acid and its variations during digestion presents serious
difficulties, because the acid enters into chemical combination
with the proteins introduced into the stomach, the pepsin and the
digestive products, and also replaces the phosphoric acid of the
phosphates contained in the food. Yet at all phases of digestion
the contents of the stomach are acid, because a much larger
quantity of hydrochloric acid is always present than is required
for combination with the proteins and the bases of the alimentary
phosphates. According to Kretschy, Eichet, Uffelmann, the
amount of free acid increases constantly during digestion in man.
Heidenhain, on the contrary, found no marked differences in the
dog in this respect.
The experiments made with the object of determining the seat
of formation of the acid of the gastric juice all point to the
conclusion that it is secreted by the glands of the mucosa of the
fundus. In fact, in the fasting animal these often exhibit an
acid reaction, while the mucous coat of the pyloric portion is
alkaline. The value of these observations is, however, impaired
by the fact that the pyloric portion always contains a denser
stratum of alkaline mucus which may neutralise the acidity of the
secretion. That the acid is not formed on the surface as Cl.
Bernard supposed, but comes from the secretory cells of the
glands, was demonstrated by Briicke on the compound glands of
the fowl's stomach. These have a central cylindrical duct into
which all the tubules of the gland open, and in which a consider-
able quantity of secretion collects. He found that under these
conditions the secretion collected within the gland has an acid
reaction.
Heidenhain by indirect arguments arrived at the conclusion
that the cells which secrete the acid are the external or border
ii EXTERNAL DIGESTIVE SECRETIONS 117
cells of the fundus glands. The pyloric glands, which are destitute
of these cells, yield a persistently alkaline secretion. Miss Green-
wood provided direct evidence in favour of this theory, by showing
that when the gastric mucosa is treated with silver nitrate the
border cells alone stain black, while all the other cells, which do
not secrete acid, are unstained.
(6) The dissolving (proteolytic] action of the gastric juice upon
proteins, which we shall examine in discussing digestion, is due to
a special enzyme, guessed at or noticed by Spallanzani, Eberle,
Beaumont, and Joh. Miiller, and to which Schwann in 1836 gave
the name of pepsin.
Wassman first isolated it in the impure state. Briicke,
Wittich, Pettit, and others, perfected the methods of extraction
and purification in various ways, but little is even yet known as
to its chemical constitution, or if it contains nitrogen, and it is
doubtful whether it belongs to the protein group.
Pepsin is an amorphous substance, greyish-yellow, odourless,
soluble in water and in glycerol, particularly if acidulated, insoluble
in alcohol, which precipitates it from its solutions. It is not
dialysable, and can thus be easily separated from the acids, salts,
and peptones, which dialyse readily (Hammarsteri).
An acid medium is an indispensable condition to the exhibition
of the digestive activity of pepsin. In neutral solution it is inert ;
it is destroyed in an alkaline medium. It neither increases nor
diminishes in quantity during the process of digestion, but
according to Griitzner it loses some of its activity.
In consequence of Wassinann's experiments, which showed
that the artificial juice prepared from the mucous membrane of
the fundus digests a given quantity of fibrin in an hour and a
half, while with that made from the mucous membrane of the
pyloric portion the same digestion requires 6 to 8 hours, it was
supposed that only the fundus glands secrete pepsin, and that the
pyloric glands secreted mucin only, the small amount of pepsin
they contain being due to infiltration of that secretion from
the fundus.
The ingenious experiments of Heidenhain and his disciples
Ebstein and Griitzner, however, showed that the pyloric glands
also secrete pepsin, although to a minor extent, because the
glandular substance is less abundant there. Langendorff, again,
found pepsin in the pyloric part of the calf's embryo. But the
most decisive proof of the digestive activity of the juice secreted
by the pyloric end was given by Klemensiewicz and Heidenhain,
who showed that this part of the stomach when isolated and
converted into a cul de sac, secretes an alkaline juice containing
pepsin, so that it is capable of digesting protein on the simple
addition of acid. According to Klemensiewicz, this pyloric juice in
acid solution usually digests better than the secretion of the
118 PHYSIOLOGY CHAP.
fundus, thus excluding the objection that the digestive action of
the pyloric juice is due to the presence in the pyloric mucosa of
some of the glands which predominate in the mucous coat of
the fundus.
(c) It was formerly held that milk coagulates, on coming
into contact with gastric mucous membrane or its extract,
owing to the gastric juice, because on merely acidifying fresh
milk its casein comes down in a flocky precipitate. But after
the experiments of Selmi and Heinz, and the exhaustive work
published by Hammarsten in 1872, and confirmed by A. Schmidt,
it was recognised that the extract of gastric mucous membrane is
able to clot milk even in a neutral or alkaline medium. This
phenomenon is therefore independent of acid and is due to a
special enzyme, distinct from the pepsin, which is called chymosin
(or renniri).
Hammarsten succeeded in separating the chymosin from the
pepsin by neutral lead acetate, which precipitates pepsin but not
chymosin. Of unknown chemical constitution, chymosin has all
the properties common to other digestive enzymes. In neutral
solutions it is destroyed at 70° C., in acid solutions at 65° C. It is
not diffusible ; its maximal activity is reached at 38-40° C. Its
action is exerted exclusively on the caseinogen of milk, and differs
from that of acids, as we shall see in the chapter on Digestion.
According to Hammarsten, one part of chymosin is able to clot
400,000-800,000 parts of casein.
Chymosin is present in large quantities in the stomach of
sucking animals, especially calves, lambs, and kids. Schumberg
found it in 15 out of 34 stomachs of adult men, and in 4 out of 6
of new-born infants. It is probably decomposed by the alkalinity
of the intestinal juice, or absorbed like other ferments, since it does
not occur in the faeces. It seems to originate like pepsin from the
pyloric glands and the chief cells of the glands of the fundus.
(d) The existence of a lipolytic enzyme in the stomach had
long been suspected (Cash, 1880 ; Ogata, 1881, etc.). Others,
however (Contejean, 1894; Boldireff, 1904), denied the value of
previous researches, carried out for the most part in vitro and with
artificial extracts of mucous membrane, or with gastric juice
extracted by the sound, and attributed the results described
either to the adulteration of the substances or to the presence of
pancreatic juice that had flowed back into the stomach. Finally,
Volhard (1900-1902) demonstrated in a series of experiments that
a very active lipolytic enzyme is produced in the stomach,
which acts particularly on emulsified fats. This enzyme is
contained chiefly in the mucosa of the fundus (in man) or of the
pyloric region (dog, cat, pig). Its action is reduced in the presence
of acids, and may be altogether inhibited ; this does not, however,
occur during the physiological digestion of fat, since the secretion
II
EXTEKNAL DIGESTIVE SECEETIONS
119
of gastric juice, and still more its acidity, is much diminished
when fat is present.
Among the many proofs of the presence of a lipolytic ferment
in the gastric mucosa, those adduced by Laqueur (1904) are of
special importance, because he makes use of Pawlow's miniature
stomach, in which there can be no question of any possible reflux
of pancreatic juice.
Laqueur points out one essential difference between the
gastric and the pancreatic lipolytic enzymes, viz. that the former is
not aided by bile, which multiplies the activity of the pancreatic
juice twenty or more times. With this reservation, the lipolytic
PIG. 39. — Cross-section of cardiac glands from human stomach during fasting. (Bohm and v.
Davidoff.) fija. a, central cell ; I, lumen of gland ; p, parietal cell ; t, connective tissue between
glands.
enzyme of gastric juice behaves like the lipolytic enzyme of succus
entericus.
XIV. Heidenhain and Ebstein, in their alcohol - hardened
preparations of gastric mucosa, studied the cytological changes
that occur in the secretory cells in hunger and in the digestive
process. These changes are quite similar to those suffered by
the cells of the serous salivary glands and the pancreas. In the
fasting state, and during the intervals of digestion, the chief cells
of the fundus glands enlarge and look clear ; while the parietal
cells are small, and triangular in section. During the first hours
of digestion, the former continue large, but become clouded ; the
latter, on the contrary, increase in size and grow round, bulging
forward to the outer surface of the tube. From the sixth to the
ninth hour of digestion, the chief cells are reduced and grow more
turbid, while the lining cells remain large or become still more
swollen. At the fifteenth hour the cells begin gradually to resume
the appearance and characters which they exhibited during hunger.
120
PHYSIOLOGY
CHAP.
These phenomena noted on the dog were confirmed for man, as
shown in Figs. 39 and 40.
Langley repeated these observations on fresh preparations of
the gastric mucous membrane, and noted changes which, although
different, lead to the same interpretation as that of Heidenhain.
In abstinence the chief cells are strongly and uniformly granular ;
during digestion they become clearer, and are differentiated into
two zones, the outer of which (f or \ the cytoplasm) does not
exhibit granules, which only appear in the inner zone. Since, as
we shall see, the extracts of gastric mucosa contain more pepsin
Fio. 40.— Cross-section of cardiac glands during digestion. (Bohm and v. Davidoff.) sos.
References as in Fig. 39.
and chymosin, according as the number of granules in the chief
cells of the fundus and pyloric glands is greater, this confirms the
theory which attributes the formation of the enzymes of the
gastric juice to these cells.
The granules seen in the cells of the gastric gland in the
fresh state do not, however, represent the enzymes of the gastric
juice, but contain the zymogens, i.e. the proteins from which pepsin
and chymosin are formed during the process of secretion.
Schiff first recognised that active pepsin comes from the
transformation of an inactive substance found in the gland cells,
which he called propepsin. The experiments of Ebstein and
Griitzner confirmed this theory. They gave the name of peptic
zymogen or pepsinogen to the inert substance which is converted
into pepsin. They found that in a watery, non-acidulated, or
glycerol extract of gastric mucosa, a certain amount of pepsinogen
ii EXTERNAL DIGESTIVE SECRETIONS 121
was extracted with the pepsin, and yielded a further quantity of
pepsin when hydrochloric acid or even sodium chloride were added.
Langley afterwards found that on extracting the gastric mucous
membrane with a 1 per cent solution of sodium carbonate, and acid-
ulating with hydrochloric acid, the extract contained pepsin, as
shown by its digestion of proteins. As sodium carbonate abolishes
the activity of pepsin, the gastric glands must contain a substance
other than pepsin, which is not destroyed by the soda solution,
and is readily transformed by acids into pepsin. This substance
is pepsinogen.
Griitzner performed a series of experiments to determine the
maximal quantity of pepsin which can be extracted by excess of
acid, with long digestion at 40° C., from the fundus and pyloric
mucous membrane of dogs killed at various hours after a meal.
He found that the pepsin is maximal in the fundus glands during
hunger, and minimal nine hours after a meal : in the pylorus glands
it increases in the first hours after a meal, reaches its maximum
at the ninth hour, and then decreases slowly. This fact agrees well
with the modifications observed in the cells of the pyloric glands,
which (unlike the changes in the fundus) increase in the first
hours after a meal, and then decrease slowly, — signifying that
in the first hours after a meal more pepsinogen is formed than
is simultaneously excreted as pepsin.
The process by which pepsinogen is normally transformed
into pepsin during the digestive period is still imperfectly known.
It was suspected, on the analogy of the transformation by the
pancreas of trypsinogen into trypsin, that the formation of
pepsin from pepsinogen might also be due to the action of an
internal secretion of the spleen, which becomes actively turgid
during digestion. This hypothesis, which Baccelli advanced in
1868, has not been fully worked out, possibly because excessive
value has been put upon the fact that animals deprived of their
spleen are able to live and digest perfectly. This objection might
be met by the further and well-established fact that it is also
possible to live without a stomach. At all events the assumption
that the spleen takes part in the formation of pepsin does not
exclude the possibility of the formation and secretion of pepsin
without a spleen.
The congested spleen of a dog in full digestion is excised, and
divided into small fragments, which are rubbed up in a mortar
with powdered glass. This paste is placed in a retort, with five
times its volume of 4 per cent boracic acid. This is digested in
a stove at 37° C. for six hours, and on filtering a transparent dark-
red fluid is obtained.
Two equal parts of this extract, 15 c.c. each, are poured into
two small flasks, with 15 c.c. solution of 04 per cent hydrochloric
acid, and | gramme of raw fibrin, ready swollen by the action of
122 PHYSIOLOGY CHAP.
0'2 per cent HC1, in which it has been standing in the cold
for 30 minutes.
In order to compare the effect of the acidified splenic extract
with that of the plain hydrochloric acid on the raw fibrin, the
same amount of swollen fibrin is placed in two other flasks, with
15 c.c. of 4 per cent boracic acid, plus 15 c.c. of 0*4 per cent HC1.
On placing the four flasks to digest in the oven at 39° C., the
fibrin with splenic extract is seen after two hours to be about half
digested, while that with hydrochloric acid alone shows no trace
of digestion. After 3| hours the other flasks are examined, and
the splenic extract is found to have digested almost all the fibrin,
while there is no trace of digestion in the fibrin left in the plain
acid solution.
This fact, many times repeated in our laboratory by Lo
Monaco and Tarulli, proves that extract of congested spleen
contains pepsin, or at any rate an enzyme with an identical
capacity for digesting fibrin in an acid medium. The living
spleen probably contains not pepsin proper but some zymogen
capable of transformation into pepsin during the manipulations
necessary for the preparation of the extract.
Hedin and Eowland (1901) further showed that the spleen
contains a proteolytic enyzme, which exhibits its maximal activity
in an acid solution. They also found it in many other organs
(lymph glands, kidneys, liver, and to a less extent the muscles
also ; infra, also Vol. I. p. 34).
XV. Two kinds of glands are found in the mucous membrane
of the Intestine — those of Brunner, which are confined to the first
portion of the duodenum, and those of Lieberkiihn, which extend
throughout the canal.
The duodenal mucosa of certain rodents also presents groups
of cells which are structurally exactly like the acini of the pancreas
(particularly the duodenal pancreas described in rabbit). Accessory
pancreases in the duodenum are not uncommon in man.
The mucous coat of the small intestine differs from that of the
stomach in having not only small ridges or folds that are obliter-
ated by distension, but also large permanent folds in the form of
crescentic projections of the mucous membrane, placed transversely
to the axis of the bowel, at a short distance from one another
(valvulae conniventes or valves of Kerkring). The whole surface,
including the valvular folds, is closely beset with villi, of varying
length, cylindrical in the jejunum, filiform in the ileum (Fig. 41),
which enormously increase the intestinal surface. The mucous
coat of the large intestine is smooth, and destitute of villi
(Fig. 42).
Between the villi of the small intestine, in every part, are
the simple tubular glands, Lieberkiihn's crypts, which resemble
the fingers of a glove, the orifices being somewhat dilated at the
II
EXTEENAL DIGESTIVE SECEETIONS
123
extremity. These crypts are more numerous in the large intestine,
owing to the absence of villi (Fig. 42).
The epithelium by which the crypts are lined is exactly
similar to that which clothes the surface of the villi. It consists
of irregular columnar cells, with a large nucleus, and striated
Fio. 41 (Left). — Section of intestinal mucous membrane (infant), shows three villi, with crypts of
Lieberkiihn. (Bohm and v. Davidoff. ) *,*. e, e, epithelium of villus ; c, connective tissue of
villus ; cc, goblet cells ; cr, Lieberkiihn's crypts ; cb, connective tissue at base of gland ; mm,
muscularis mucosae.
Fio. 42 (Right).— Section of mucous membrane of human colon, showing three crypts of Lieber-
kilhn. (Bohm and v. Davidoff.) ^ja. e, epithelium ; I, lumen of > gland ; cc, goblet cells ; ti,
interglandular tissue ; ta, areolar tissue of mucous membrane ; mm, muscularis mucosae.
cuticular layer, and a somewhat flattened end which is attached
to the surface of the basement membrane, without extending
(as was formerly supposed) into the reticulated tissue of the villi.
Leucocytes are seen here and there between the epithelial cells
(Fig. 43).
Goblet cells produced by mucoid degeneration of the ordinary
columnar cells are seen between the latter, the outer half of these
124
PHYSIOLOGY
CHAP.
swelling and filling with mucus, which bursts through the free
end, and is discharged externally. The number of goblet cells
varies with the animal and the state of abstinence or digestion.
They are specially abundant in the mucous coat of the large
intestine, while in the small intestine they are wanting altogether.
Brunner's glands are situated in the upper part of the duodenal
mucosa; they also extend beyond the pyloric antrurn of the
stomach, and may be found in the mucous membrane between the
crypts of Lieberkiihn. They are small acino- tubular glands,
which consist of branching and twisted tubules, ending in pro-
longed dilatations or alveoli, which unite into a secretory duct
lined with epithelial cells similar to those of the alveoli. These
cells resemble those of the pyloric glands of the stomach (Fig. 44).
FIG. 43. — Columnar epithelium from rabbit's intestine. (Schiifer.) A, two isolated cells after
maceration in very weak chromic acid, showing striated border, and the bright disc which
separates them from the cell protoplasm ; n, nucleus with internuclear network ; a, thin pro-
jection of cell, which probably fitted between two adjacent cells. B, row of columnar cells
from intestinal villus of rabbit ; str, striated border ; if, smaller cells of the nature of lymph
corpuscles, between the epithelial cells.
Little is known about the secretion of Brunner's glands.
According to Hirt, they undergo the same modifications during
digestion as the pyloric glands ; in the fasting state their
cells are comparatively large and clear, ill digestion they are
small and clouded. Grlitzner found that at different distances
from the pylorus the glands are in a different functional state.
A watery extract of Brunner's glands, freed as far as possible
from the duodenal mucosa, contains (according to Krolow) a
ferment which digests fibrin, but not boiled egg-albumin, in an
acid medium. They must therefore secrete pepsin like the
pyloric glands. According to Grlitzner, the enzyme (or zymogen)
accumulates during hunger, and discharges during digestion, when
the secretory cells become smaller. Mendeldorp also finds a
diastatic enzyme in the extract of gland substance. From the
little we know as to the nature of the secretion of Brunner's glands
their product appears to mix with the acid chyme which passes
rhythmically from the stomach to the duodenum, through the
pyloric valves, after the first hours of digestion.
n
EXTEKNAL DIGESTIVE SECEETIONS
125
XVI. To study pure succus entericus (which is the product of
all the secretory cells of the small intestine, both in the external
epithelium of the villi, and in the epithelium which lines the
crypts of Lieberkiihn internally) it is necessary to isolate a loop
of intestine, closing one end by stitches while the other is sutured
to the wall of the bowel, after bringing together the two ends
of cut intestine, so as to re-establish the continuity of the gut
(Thiry's method). It is more convenient to stitch both ends of
the intestinal loop, separately, to the abdominal walls, so as to
PIG. 44. — Section of mucous membrane through commencement of duodenum at pylorus. (Klein.)
v, villi ; 6, apex of a lymphoid nodule ; c, crypts of Lieberkiihn ; TO, muscularis mucosae ; s,
Brunner's glands cut more or less obliquely ; d, ducts of pyloric glands of stomach ; g,
oblique section of same ; t, deeper tubes in submucous tissue, corresponding with Brunner's
glands of intestine.
make two fistulous apertures communicating with each other by
the loop (Vella's method).
During inanition, according to Boldireff (1905), the secretion
from Vella's loop is scanty, with a rhythmical maximum and
minimum cycle of about 2 hours — 5-6 c.c. of succus entericus can
be collected altogether in 8 to 10 hours.
Some authors say that mechanical stimuli (sounds, sponges,
etc.) introduced into the loop are able to excite a true secretion
there, even during hunger. But according to U. Lombroso,
these stimuli only excite a small increase in the flow of secretion,
which is probably due to increased peristalsis.
Electrical stimuli are more effective than mechanical. The
effects of chemical stimuli are better known (Frouin, Lombroso,
126 PHYSIOLOGY CHAP.
Delezenne). When acetic, hydrochloric, lactic, or weak carbonic
acid is injected, a certain amount of secretion is observed. The
secretion obtained with these acids is serous, fluid, colourless if
the solution is weak, lemon-yellow or pinkish if more concentrated.
It has a very slight lipolytic action. Acids combined with pepsin
or with the alimentary proteins also excite enteric secretion. The
higher fatty acids dissolved by bile, and soap solutions (which at
once set free the fatty acids when introduced into the loop of
Vella) are more powerful than any other substance in exciting
enteric secretion.
Besides being more copious, the secretion excited by the
higher fatty acids (oleic acid) has quite different physical
characters ; it is dense, ropy, and contains a number of enzymes.
Bile and alkalies produce no noticeable secretion.
Masloff obtained rich secretions from the intestinal fistula
(preternatural anus) in dogs, with subcutaneous injections of
pilocarpine. Vella confirmed the same on his isolated loop of
intestine.
The physiological conditions for the secretion of succus
entericus during digestion are as follows. In the isolated loop,
where no food can penetrate, a secretion of juice (more or less
abundant according to the nature of the food) is seen some time
after the meal. This tends to increase for a certain time, and
only ceases at the seventh to eighth hour of digestion. The time
at which the secretion reaches its maximum varies greatly, and
seems to depend on the varying nature of the food. The total
quantity of secretion that can be collected after 8 to 10 hours
does not exceed 8 to 12 c.c.
Data in regard to the chemical composition of the succus
entericus differ with the animal used and the method by which
it is collected. The fluid that issues from the isolated loop of the
lower tract of the small intestine (ileum), is, according to Thiry,
thin, opaline, yellowish, strongly alkaline, of specific gravity TO 10.
It contains —
Water 97-2-97-9 per cent.
Solids 2-2- 2-8 „
Protein 0'7- 0-12 „
Ash 0-7- 0-8 „
In addition to sodium chloride the ash contains large quantities
of sodium carbonate, as on adding acids t the succus entericus
effervesces. It always exhibits a few enzymes, to which its weak
digestive powers are due. Its action is diastatic on starch and
glycogen, invertive of saccharose into dextrose, curdling on milk,
emulsifying on fats, similar to that possessed by all alkaline
fluids. Succus entericus is further credited with the property of
splitting up fibrin, which cannot be very important, but Schiff,
ii EXTERNAL DIGESTIVE SECRETIONS 127
and afterwards Vella, stated that it had the property of digesting
all proteins, which (if true) would raise the physiological value of
succus entericus to that of pancreatic secretion. The best work
with artificial digestions of succus entericus and boiled egg-
white, flesh, and proteins in general (putrefaction being avoided),
has, however, given entirely negative effects (Thiry, Wenz, Boccardi,
Malerba and Jappelli, Bastianelli, Klug, Pregl, and others).
But if succus entericus is incapable of digesting coagulated
albumin and natural proteins, it does contain a special enzyme,
Cohnheim's erepsin (1902), which acts on peptones, and splits
them into their final crystallisable products. All authors do not
agree in giving erepsin the importance which Cohnheim attributes
to it. Kutscher maintains that tryptic digestion alone is capable
of completely splitting the proteins until the biuret reaction
disappears. Bottazzi — experimenting with intestinal extract —
denies, on the strength of his results, that this particular pro-
teolytic enzyme is secreted by the intestinal mucosa. He refers it
to the activity of the trypsin secreted by the pancreas, and left to
a greater or less extent adherent to the intestinal mucosa. We
shall return to this in discussing intestinal digestion.
The existence of a lipolytic enzyme (or lipase) in succus
entericus was long a subject of discussion. Early experimenters
(Vella, Schiff) were inclined to admit its presence ; but later work
with the natural secretion, given necessary precautions for pre-
venting putrefaction (Malerba, Jappelli, Bastianelli, Pregl, and
others), proved that there was no true lipolytic action, or that
it could only be minimal. Thus Lombroso, on investigating
the succus entericus secreted naturally by a loop of Vella during
digestion, or after injections of pilocarpine, observed that it had
a very slight lipolytic activity. He found, however, that the
intestinal secretion poured out in large quantities when a higher
fatty acid is introduced into the loop, is actively lipolytic to an
extent approximating to that of the pancreatic secretion.
But the lipolytic enzyme of intestinal, unlike that of pancreatic,
juice is not aided in its action by bile. Lombroso's observation
cannot be met by the objection made to earlier workers, viz. that
the positive result is due to the presence of pancreatic enzymes
in the mucous membrane of the intestine, for the succus
entericus exhibiting this lipolytic activity is excited only by
definite stimuli (fatty acids), and does not diminish even when,
by repeated experiment, many hundred c.c. of juice have been
secreted by the Vella's loop.
Besides these enzymes, which are normally contained in the
mucous coat of the intestine, there is in mammals during the
secreting period an enzyme (lactase) capable of transforming
lactose (which is not directly utilisable by the body) into glucose
and galactose (Beyerick, Fischer and Niebel, Portier, Orban).
128
PHYSIOLOGY
CHAP.
Sisto showed that the mucous membrane of adult mammals,
which does not normally contain lactase, can produce this enzyme
after a diet containing a large quantity of lactose, extending over
several weeks. Birds, too, can be induced to secrete lactase by a
still longer period of alimentation.
The glandular crypts of the large, unlike those of the small,
intestine do not secrete any digestive juice. The food -stuffs
introduced into the large intestine, after making an anus preter-
naturalis, undergo no diges-
tive modification. It is
impossible, by any means,
to obtain any considerable
quantity of secretion from
this part of the gut. The
small amount that can be
obtained by little sponges
enclosed in wire capsules
introduced by the fistula
is clear, gelatinous, neutral
in reaction, laden with floc-
culi of mucus (Klug and
Koreck). Injections of pilo-
carpine, which exaggerate
all secretions of the gastro-
intestinal tube, change the
appearance of the mucino-
genous epithelial cells of
the large intestine, so that
they exactly resemble those
which line the crypts of
the small bowel (Fig. 45).
FIG. 45.— Glands of large intestine of rabbit. (Hoiden- This fact, noted by Heiden-
tog rest' after c°pious secreti°n °f mucus : B' after hain's pupils, shows that
the glandular epithelium of
the large intestine is more subject than that of the small bowel to
mucosal changes during rest, and that during secretory activity the
mucus formed is excreted, and the primitive cells which predomi-
nate in the small intestine are regenerated, by a new formation of
the cytoplasm which surrounds the nucleus. Secretion of mucus
(which is very useful in facilitating the expulsion of the faecal
matters, which harden in the last part of the intestine by
absorption of water) thus seems to be the only well-ascertained
function of the secretory cells of the mucous coat of the large
intestine.
XVII. Little definite is known as to the dependence of the
intestinal secretion on the nervous system. According to Thiry
and others, stimulation of the vagus produces no effect. According
ii EXTEENAL DIGESTIVE SECKETIONS 129
to Budge, extirpation of the caeliac plexus causes increase of
intestinal peristalsis, with increased secretion of succus entericus.
Moreau's results are more important (1868). After making an
intestinal loop, he cut the mesenteric nerves which accompany
the vessels of the loop, and at once, or shortly after, saw an extra-
ordinary amount of juice secreted in the loop, but not in the
contiguous parts of the intestine in which the nerves were intact.
This excessive secretion may amount to ^r of the body- weight ; it
lasts for several hours, becomes less after 4 to 5 hours, and only
ceases after 24 hours. The secretion is at first a clear liquid,
which presently becomes clouded with flocculi of mucus. Some-
times it looks milky, and it contains large quantities of detached
epithelial cells.
This enormous formation of intestinal juice (which has the
same properties as the normal secretion collected in the loop of
Vella) is pot explained by simple paralytic dilatation of the vessels.
We must assume that the phenomenon depends on lapse of control
by special nerves, of the secretory processes of the epithelia.
Since the secretion is in this case the effect, not of excitation, but
of severance of the nerves, we are forced to assume that the latter
inhibit the intestinal secretion, i.e. normally serve to keep it in
bounds by their tonic action. Nothing similar has, however, been
produced on stimulating the nerves to these glands. Moreau's
phenomenon plainly recalls 01. Bernard's discovery of paralytic
secretion for the submaxillary gland, and presents the same
difficulties of interpretation.
According to the supporters of Bayliss and Starling's theory
(see p. 90 et seq.), the intestinal secretion, also, is due to the produc-
tion by the duodenum of secretin, which, on absorption and circula-
tion in the blood, comes into contact with the intestinal epithelia
of the gut, and excites them to secrete. This theory rests on
certain observations on secretion in a Vella's loop after the
injection of secretin. We have already pointed out the inadequacy
of these observations, and it is unnecessary to recapitulate the
objections in reference to intestinal secretion also.
According to Delezenne and Frouin, the succus entericus, after
undergoing the action of acids in the intestinal cavity, is reabsorbed
and excites secretion in other parts of the intestine. They
observed that succus entericus, acidified with hydrochloric acid
and subsequently neutralised and injected into the vein, excites
an abundant secretion. Moreover, in a dog provided with two
Thiry's intestinal fistulae, the introduction into one of the
fistulae of substances that excite secretion (hydrochloric acid, ether,
water) produced secretion in the other fistula also. This secretory
action at a distance is determined, according to Frouin and
Delezenne, not by the propagation of secretory stimuli by nervous
paths, but by the action of the reabsorbed succus entericus.
VOL. II K
130 PHYSIOLOGY CHAI-.
U. Loinbroso opposes this theory by a number of data worked
out in our laboratory. He observed the secretion in a Vella's
loop, made at a certain distance from the duodenum, on many
occasions, and for many hours. He has proved that there is
always a very scanty secretion (4-6 c.c. of juice) in 6 to' 8 hours, even
after meals that are rich in flesh and fat, or consist of fat alone.
But if a solution of oleic acid or of soap is introduced directly into
the loop, an abundant secretion is at once called out. With 25 c.c.
oleic acid dissolved in bile, it is possible in a few minutes to obtain
30-40 c.c. or more of succus entericus.
It is a familiar fact that soap and fatty acid dissolved in bile
are found throughout the intestine after giving fats. If no
secretion occurs in Vella's loop, even after the digestion of large
quantities of fats, this must mean that the hormones which
activate secretion in the isolated tract of the loop are either not
produced or not absorbed during digestion.
But if it be proved that enteric secretion is not excited by
hormone stimuli ; if, on the other hand, Lombroso's observations
tell against the hypothesis that the mesenteric nerves convey the
secretory stimuli to the intestinal mucosa (as we said above, they
appear rather to have the task of inhibiting the intestinal secretion),
the question still remains open as to whether the said secretion
results solely from the direct action of chemical stimuli, or if these
may determine it by reflex paths from other regions that are not
directly excited, e.g. the stomach.
Lombroso's observations on the ordinary Vella's loop have not
solved the problem, because the operative act completely destroys
the relations of continuity of the nerves that run throughout the
extent of the intestinal walls, so that they can no longer propagate
the secretory stimuli.
Lombroso has accordingly modified his method of operation.
He separates a fairly long segment of intestine (50-80 cm.) as if
making a Vella's loop. After suturing the two extreme ends of
the divided portion to the abdominal walls, he attaches 3-4 cm. of
the middle part of the loop to the same wall. When adhesion
takes place, i.e. in 3 to 4 days, he slits up the middle of the loop so
as to bring it into relation with the exterior. This produces twin
loops of Vella, which preserve connection with the nerve plexuses
that run along the coats of the intestine.
On introducing a substance that excites secretion into the
first loop, the second loop does not secrete unless the same sub-
stance is made to pass into it by bringing the two lips together.
This indicates that direct action of the proper chemical stimuli
on the mucous membrane is necessary to excite the intestinal
secretion.
XVIII. The Liver in its structure and functions is a gland,
which in adult man weighs about 1579 grms. (1526 grms. in
II
EXTEENAL DIGESTIVE SECRETIONS
131
woman), with an average volume of 1720 c.c. (Vierordt). This
gigantic development, and the intimate relations by means of the
portal system with the gastro-intestinal system, point to the true
physiological function of the liver as a laboratory for complex and
mysterious chemical operations, in which the preparation of the
bile that is formed and poured out into the gall-bladder and
duodenum is probably only a secondary process. The amount of
bile secreted daily by man rarely, in fact, exceeds 800 grms., while
the little parotid gland (which only weighs 24-30 grms.) daily
discharges as much as 1000 grms. of secretion. In this chapter,
however, we shall only consider the liver as the organ of Hie
FIG. 46. —Diagram of fragment of liver from a six-months' foetus. Silver chromate method.
(G. Retzius.) The bile canaliculi are stained black. They have not yet anastomosed, and
give off minute twigs between the hepatic cells, with a terminal dilatation.
secretion. Its complex metabolism and internal secretions will be
discussed elsewhere.
Morphologists regard the liver as a tubular retiform gland,
consisting of cells arranged round glandular spaces which form a
very fine capillary network, the bile canaliculi. These appear to
have no membrane propria, and to be merely grooved out between
adjacent liver-cells, running on into the bile ducts, which have
walls and unite in larger and larger branches, till they converge
into the excretory, hepatic duct.
In the lower vertebrates, and the embryos of birds and
mammals, the liver is a tubular gland. The tubules do not
anastomose to form a network, but end in small branches, the ends
of which are often enlarged and penetrate into the hepatic cells
(Fig. 46). In adult vertebrates, on the contrary, the ramifications
of the canaliculi do anastomose to form an intercellular network,
which communicates with special vacuoles in the cell protoplasm
132
PHYSIOLOGY
CHAP.
(Fig. 47). Whether these vacuoles leading into the network of
the bile canaliculi, and first observed by Pfliiger and by Kupffer,
and confirmed by others, are permanent structures, or whether
they are only formed at the moment of secretion, or produced
artificially by the staining fluids injected through the bile ducts
(which may fairly be excluded seeing that nothing of the sort has
been met with in other injected tissues), is unknown.
The peculiar structure of the hepatic parenchyma is determined
by the arrangement of its blood-vessels, which (with the lymphoid
connective tissue connected with Glisson's Capsule) constitutes
the scaffolding or framework of the hepatic cells. Unlike all
other organs, the afferent vessels of the liver consist not only of an
Fio. 47. — Section of liver from adult animals, with injected bile capillaries. (Kupffer.) A, bile
canaliculi of rabbit's liver, artificially injected from hepatic ducts with Berlin blue solution.
They give off minute projections like a pin's head, which penetrate into the protoplasm of
the liver cells. B, the same from frog's liver, after natural injection with sulphindigotate
of soda. Here the projections form a network of fine fibrils inside the hepatic cells, with
terminal dilatations.
artery — the hepatic artery, but also of a vein — the portal vein,
which is formed by the union of the efferent veins from the
stomach, intestine, pancreas, and spleen ; these form a venous
trunk with exceptionally robust and muscular walls, and a much
larger calibre than the hepatic artery. The efferent vessels are :
the hepatic veins, with thin walls, which arise in the portal
capillaries, run towards the posterior surface of the liver, and open
into the inferior vena cava ; and the lymphatics, which are large
and numerous in the liver, originating in the lymph sinuses round
the portal capillaries, and which accompany and to a large extent
enclose the branches of the blood-vessels, and leave by the portal
fissure with the portal vein, the hepatic artery, and the 'bile or
hepatic duct. This last leads by the cystic duct to the gall-
bladder, and the junction of the two ducts (hepatic and cystic)
form the common bile duct or ductus choledochus, which pours
n
EXTEENAL DIGESTIVE SECKETIONS
133
the bile into the duodenum during digestion, 7-10 cm. from the
pylorus.
By a special system of distribution, capillary formation, and
reconstitution of these vessels, the hepatic parenchyma is divided
into a number of lobules or acini varying in diameter from
1 to 2 mm. — polyhedral or spheroid in shape, — which profoundly
modify the original tubular form of the gland. The branches of the
PIG. 48.— Section of liver lobule, with blood-vessels and bile-ducts injected. (Cadiat.) 6, I, inter-
lobular veins ; a, intralobular vein ; c, interlobular bile-ducts, with which the bile canaliculi
of the lobule are connected. The latter are only injected in the peripheral parts of the
lobule.
portal vein and hepatic artery penetrate as the interlobular veins
and arteries between the lobules, sending twigs to the interior
of the lobule which soon form a dense capillary network, from
which the intralobular veins re-form, and lead into a central vein
(Fig. 48). The intralobular and central veins are the beginning
of the efferent hepatic veins, which traverse the lobule in a radial
direction, and unite in the sublobular veins ; these form into larger
and larger branches, converging towards the posterior surface of
the liver, where they open, as we said, into the inferior vena cava.
134
PHYSIOLOGY
CHAP.
The interlobular course of the hepatic duct is similar to that
of the portal vein and the hepatic artery, but its interlobular
branches form a much finer network of canaliculi than that
formed by the blood-vessels, as shown in Fig. 48.
The hepatic cells lie in the interstices of the network of blood
capillaries, and round the closer meshes of the bile canaliculi.
They are polyhedral, 17-22 p, in diameter, destitute of cell
membrane, and have a clear nucleus, with intranuclear network,
and one or two nucleoli.
The finely reticulated cytoplasm, the deutoplasmic content,
and the aspect as a whole of
the liver-cells change consider-
ably (as we shall see below)
according to whether they are
examined in the fasting state
or after food. Fig. 49 shows
the relations and respective size
and position of the hepatic cells,
the network of blood capillaries,
and the finer network of bile
canaliculi.
The nerves to the liver are
branches of the vagus and of
the solar plexus of the sym-
pathetic. They enter by the
portal fissure, accompanying the
hepatic artery and the portal
vein. They consist partly of
medullated,partly of non-medul-
lated fibres. The latter are dis-
Fio. 49.— Section of rabbit's liver after injection tributed almost exclusively to
of intracellular network of bile capillaries. , •, . j , , • j_i
(Bering.) Thick section, showing two or the arteries and the veins ; the
three layers of cells and relative size and fnrrnpr PT1fpr fV>P InVmlpcj wViPTP
position of blood capillaries, b, 6 ; bile canali- lOrmer enter HlC 10DU16S, WHere
cuii, c, c ; and hepatic cells, e, e. they lose their medullary sheaths
and ramify between and over
the cells, in a network of fine filaments (Fig. 50).
XIX. The external secretion of Bile produced by the liver
is distinguished from the four secretions above described, by
being continuous — although it presents considerable fluctuations,
particularly in relation to the state of digestion or fasting ; by
having no specific enzymes; and by being apparently regulated
merely by the hydraulic conditions of the hepatic circulation and
absorbed digestive products, independent of any direct influence
of secretory nerves, to which the other digestive secretions proper
are subordinated. For all these reasons the biliary secretion
presents more analogy with the secretion of urine as performed by
the kidneys than with the secretions of digestive juice which we
II
EXTERNAL DIGESTIVE SECRETIONS
135
have been considering. But there is one fundamental difference
between the biliary and the urinary secretions, i.e. the specific
components of bile are, as we shall see, formed exclusively by the
metabolism of the hepatic cells, while the constituents of the urine
eliminated by the kidneys are mainly pre-formed in the blood, and
represent the products of the metabolism of other tissues.
The bile secretion is studied in animals by making a fistula of the gall-
bladder (Schwann, 1844), either leaving the bile-duct free or tying it. In
a
FIG. 50. —Plexus of nerve fibrils within hepatic lobe of pigeon. Methylene blue method.
(Korolkow.) a, a, axis-cylinders of nerve-fibres passing between cell-trabeculae of the lobule ;
b, 6, fibrils ramifying over the cells ; c, c, hepatic lobules.
.the first case (incomplete fistula), if the fistula of the gall-bladder is properly
closed, the bile can flow, as normally, into the duodenum ; in the second
(complete fistula), it is compelled to flow out to the exterior. In order
to study the process of bile secretion, it is necessary to make the fistula com-
plete and permanent, so as to be sure that the whole of the bile secreted
escapes by the orifice of the fistula. In cases of fistula of the gall-bladder
observed on man (Ranke, 1871, down to Noel Paton and J. M. Balfour,
1891), the fistula is always incomplete, and in these, cases it is seen by the
colour of the faeces that some of the bile secreted by the liver does not
pass through the opening of the fistula, but escapes by the bile duct and
discharges into the duodenum.
The innumerable experiments on bile secretion by complete or
incomplete fistulae of the gall-bladder in man and animals have
136 PHYSIOLOGY CHAP.
yielded very divergent results, especially as regards the influence
of the various foods ingested. Heidenhain recognised these dis-
crepancies, but held to the opinion that the secretion of bile not
only increases during digestion, but exhibits two rises during this
period, one 3-5 hours, the other 13-15 hours after a meal. Not
being satisfied with these results, which differed from those
obtained by Spiro with Ludwig, we advised Baldi in 1881 to
repeat the same experiments in our laboratory, on dogs with a
complete biliary fistula, when they had quite recovered from the
operation and were in good physiological condition. He found a
surprising irregularity in the flow of the bile secretion, and was
unable to show any constant influence of digestion in general, or
of the nature of the foods administered to the animals.
On comparing the quantity of bile secreted in the space of a
few hours before and after a meal, he obtained a certain increase
during the period of digestion ; but the difference was not very
conspicuous, and may be interpreted as the effect rather of
increased blood-supply during digestion than of secretory excita-
tion of the hepatic cells. The entirely negative results obtained
with the so-called cholagogues (podophyllin, rhubarb, jalap, pilo-
carpine, aloe, etc.), in comparison with the immediate and con-
spicuous increase of the biliary secretion observed after injecting
ox bile, caused Baldi to revive the ancient doctrine, of Aristotle,
Galen, and Morgagni, according to which the bile is a complex of
the products excreted by other tissues, the hepatic cells being only
the instruments of their selective elimination, as the cells of the
renal canaliculi are for the urinary products.
Later work has shown this position to be untenable; but it
was certainly owing to Baldi's experiments that attention was
once more directed to this important problem.
With regard to the process of bile secretion and the influence
exerted on it by various foods, Barbara's results (in a series of
publications, 1894-98, which sum up the methodical researches he
made in Albertoni's laboratory) are particularly interesting.
Barbera carried out a number of comparative experiments
under identical conditions on dogs with a complete biliary fistula,
healed some time previously (at least four months) from the opera-
tion, when they had regained their initial body -weight, and
were accustomed to remain quietly in a Cyon's holder. The
day before each experiment, the dogs received a scanty meal of
mixed food, which was always identical in quality and quantity.
Twenty-four hours after, the animal was fixed to Cyon's holder,
and about three hours after fixation received the test meal, which
varied in its nature in different experiments on the same animal.
By this mode of procedure, it was possible to avoid any influence
of the preceding meal on the flow of secretion, while the effect of
the test meal was fully brought out.
II
EXTEENAL DIGESTIVE SECKETIONS
137
Barbara's results are plain from the accompanying diagram
(Fig. 51). As it shows, during an absolute fast the quantity of
bile secreted in each hour oscillates slightly round a minimum
(4-5 grms. in a dog of about 20 kilos.). This amount of bile,
secreted during hunger, is not perceptibly affected by the ingestion
of water, even in considerable quantities, provided the animals had
FIG. 51. — Diagram to show course of bile secretion in fasting and with different kinds of diet, in a
healthy dog of 20 kilos., operated on four months previously by complete and permanent
fistula of gall-bladder. (Barbera.) Continuous line shows course of bile secretions during
abstinence or injections of water only ; the line of crosses, after injection of 500 grms. horse-
flesh ; the dotted line, after ingestion of 100 grms. cane-sugar ; the broken and dotted line,
after ingestion of 100 grms. fresh butter ; the broken line, after mixed diet of 300 grms. flesh,
30 grms. butter, and 300 grms. bread.
not previously been deprived of water for any length of time, in
which case the bile is denser than usual.
A meal of protein is followed by a very marked increase in bile
elimination, which commences after about 30 minutes, reaches its
maximum after four hours, and then declines till it ceases entirely
in about fourteen hours.
A meal of fats is followed by marked increase in bile
secretion, which commences after about one hour, reaches its
maximum after about five hours, and drags on with a slow decline
till it stops after about twenty hours.
A meal of carbohydrates is followed by a slight increase in
138 PHYSIOLOGY CHAP.
secretion, which commences suddenly, reaches its maximum at the
third hour, and ceases entirely during the sixth hour.
After a mixed meal the increase may be marked, when proteins
and fats predominate (see diagram), or slight, as when the carbo-
hydrates predominate.
These striking results, along with what is known of the
metabolism of the hepatic cells, suggest interesting considerations,
which we shall discuss in a future chapter, in studying the liver
as an organ of internal secretion. Here we must confine ourselves
to stating that the formation of bile is not activated by the
presence of food-stuffs in the gastro-intestinal tube, as a reflex
along nerve paths, but only when the alimentary substances
reach the liver by way of the portal vein, after digestion and
absorption. In fact, the experiments of Barbera show that the
influence of the food on bile secretion is conditioned by digestion
and absorption. When injected per rectum, those food-stuffs only
increase the secretion of bile which are absorbed (carbohydrates
and proteins), not such as are non-absorbable by this method
(fats).
The production of bile continues to a less extent, even when
the products of food digestion no longer reach the liver. During
a fast protracted till death occurs from inanition (Chossat, Luciani,
Albertoni), the amount of bile secreted gradually diminishes,
but is not arrested, up to the end. Albertoni, who studied
this phenomenon methodically (1893), saw that in fasting the
quantity of bile secreted diminished daily, while its specific gravity,
i.e. the relative amount of solid residues, nitrogen, and sulphur,
increased.
Bile is also formed from the third month of intra-uterine life,
and during the lethargic period of hibernating animals, though
only in small quantities (as in the fasting state).
According to Brand (1902), who studied the secretion and
composition of human bile in nine cases of fistula of the gall-
bladder, the amount of bile that flows out in man (from a complete
fistula) varies considerably from hour to hour. The daily amount
oscillates between 500 and 1100 c.c. The biliary secretion dimin-
ishes in the night, and falls to its minimum in the early hours of
the morning ; it then increases rapidly, reaches its maximum
about noon, and is usually succeeded by another maximum in the
evening. G. Galli (1906) obtained similar results in an analogous
case of fistula of the gall-bladder in a woman.
This proves that the secretion of bile, unlike the other secretions
which we have previously studied, is not co-ordinated with the
digestion of foods, since it is effected under conditions in which no
digestion takes place in the intestine, and increases when digestion
and absorption have already occurred. Biligenic and cholagogic
materials, such, i.e., as are capable of being transformed in the liver
ii EXTEENAL DIGESTIVE SECEETIONS 139
into bile, or of exciting the secretory metabolism of the hepatic
cells, are continuously circulating in the blood that courses through
the liver, independent of the digestive products absorbed.
Evidently these bile-forming and eliminating substances must
be katabolic products, both of the cells circulating in the blood and
of the fixed tissue-cells. This is proved by the fact that transfusion
of blood (particularly when heterogeneous) conspicuously increases
the production of bile (Landois). The so-called cholagogues of the
pharmacologists are ineffective, save in so far as they destroy the
cells of the blood and tissues, — the waste products being then
elaborated by the liver (Noel Paton, 1886). If dogs with fistula
of the gall-bladder are made to ingest the products of nitrogenous
consumption, e.g. extractives of meat and uric acid (provided this
be rendered soluble and absorbable in the form of potassic urate),
there will be a constant augmentation of the bile secretion, with
increase of urea in the urine. Ingestion of urea, on the contrary,
even in very large doses, does not excite biliary secretion. When
it reaches the liver, the urea is entirely taken up by the central
veins of the lobules, and excreted by the kidneys. This fact,
established by Barbera (1898), proves the continuity of the bile
secretion, showing that the extractives and the uric acid which are
never absent from the blood of animals, either under ordinary
conditions or in fasting, excite metabolism in the hepatic cells, by
which they are transformed into urea. Urea, on the contrary, has
no action on the liver-cells, because it is the end-product of the
oxidation of nitrogenous substances, and is excreted unchanged by
the kidneys.
Barbara's later work (1902) also confirms this theory. Instead
of administering the various substances by the mouth or rectum,
he injected them subcutaneously in dogs, and studied their action
on the bile secretion. Injections of distilled water, of solutions of
glucose (up to 10 per cent), of medium doses of sterilised olive oil,
and of 5 to V per cent solutions of somatose had no effect on the
elimination of bile. On the other hand, he observed increase of
the secretion on injection of more concentrated solutions (glucose
20 per cent and more, somatose 10 per cent and more), or of large
doses of non-sterilised olive oil. But since these last injections
simultaneously induce local phenomena of irritation at the point
of injection, accompanied by increased elimination of urea and
slight rises of temperature, Barbera came to the conclusion that
the increase of bile secretion depends not on any direct action of
these substances on the hepatic cells, but, indirectly, upon the
increased destruction of proteins, the cleavage products of which
excite augmentation in the biliary secretion of the liver.
Another fact worth noting is that the secretion normally
poured by the liver into the gall-bladder is not all newly-formed
bile : a considerable part of it is only bile reabsorbed from the
140 PHYSIOLOGY CHAP.
intestine, conducted back to the liver by way of the portal vein,
and eliminated once more from the liver by the bile ducts. This
kind of entero-hepatic circulation of the bile was worked out
particularly by Schiff, Lussana, Baldi, Tarchanoff, and Wertheirner.
It is only necessary to give bile by the mouth, or to inject it
directly into the duodenum, of a dog with a fistula of the gall-
bladder, in order shortly after to see a flow from the fistula,
proportionate to the amount of bile administered. Again, on
injection by the veins, the bile is not excreted by the ureters but
entirely by the hepatic duct, if a moderate amount be injected.
On injecting ox-bile, which is green (owing to the large preponder-
ance of biliverdin), the secretion flowing from the biliary fistula of
the dog loses its orange colour (due to preponderance of bilirubin),
and assumes the hue of ox-bile (Baldi). This fact demonstrates the
specific excretory function of the hepatic cells for the constituents
of bile, which is of great importance, since it extends not only to
these but also to many other toxic and medicinal substances
introduced into the gastro-intestinal tube, which on reaching the
liver are carried back to the intestine with the bile (Lussana,
Moroni and Dyall, Acqua, Schiff, and others). Barbera (1898)
rightly insisted on a phenomenon which is not easy to explain by
known laws of physics and chemistry. If fasting dogs with a
fistula of the gall-bladder are made to ingest large quantities of
bile and urea together, then although both substances are taken
up by the portal vein, and carried to the liver, the whole of the
bile is constantly eliminated by the bile-ducts, while the whole of
the urea passes into the capillaries which lead to the central veins
of the lobule, and is excreted by the kidneys. To account for this
fact, he assumes a differentiation into two parts of the hepatic cells ;
the one in contact with the bile canaliculi, the other in relation with
the blood capillaries which lead to the central veins of the hepatic
lobules. These two parts must have different excretory functions,
due possibly to a difference in cytological structure, which we are
unable by our present methods to detect. But without invoking
any unfounded hypothesis, the fact may be explained as depending
on the selective attraction of the hepatic cells for biligenic sub-
stances (positive chemotaxis), while they repel urea (negative
chemotaxis).
XX. The biliary secretion can be modified not only by the
composition of the blood that circulates round the hepatic cells,
but also by the amount of blood that flows to the liver, and the
vascular tonicity of the portal vein and hepatic artery. The
augmented secretion that occurs during digestion is partly due, no
doubt, to the active vascular dilatation which accompanies the
secretory work of all organs that function during the digestive
processes.
Just as the bile secretion is promoted by a rapid and abundant
ii EXTEKNAL DIGESTIVE SECKETIONS 141
flow of blood through the liver, so the interruption of the blood-
stream by ligation of the hepatic artery and portal vein arrests it
(Kohrig). After tying the hepatic artery alone, bile may still be
copiously secreted, fed from the portal blood alone (Simon, Schiff,
Schmulewitsch, Asp). The hepatic artery supplies the nutrient
vessels of the gall-bladder, bile-ducts, and interlobular branches of
the portal system, while it takes no direct part in the formation
of the intralobular network of blood capillaries. For this reason,
ligation of the hepatic artery gives rise after some time to the
formation of multiple necrotic foci in the liver, the larger of which
are converted into cysts, while the smaller are replaced by con-
nective tissue, so that hepatic cirrhosis develops (CohnKeim and
Litten).
The rapid and complete occlusion of the portal vein speedily
produces the death of the animal, owing to stasis and excessive
congestion of blood throughout the portal system. But if one
branch alone be tied, leading to one lobe of the liver, the biliary
secretion may continue in that lobe, fed solely by the artery
(Schmulewitsch, Asp). The same is also seen when ligation is
gradually applied to the entire portal trunk (Ore, Osier) ; also
when the blood of the hepatic artery is led directly into the
opened portal vein (Schiff).
When arterial pressure is lowered, either by haemorrhage, or
from vascular paralysis consequent on section of the cervical
medulla, there is diminution or arrest of the bile secretion. It
increases, on the contrary, after section of the splanchnic, because
in this case, although arterial pressure is diminished, the flow of
blood to the liver is increased, owing to paralytic dilatation of the
vessels at the roots of the portal system. By a diametrically
opposite effect, the bile secretion diminishes with electrical excita-
tion of the cord, of the splanchnics, or on strychinisation of the
animal (Heidenhain, I. Munk).
Circulation in the blood-vessels of the liver can be modified,
not only by the effects of constriction or dilatation of the roots of
the portal, or by increase or decrease of aortic pressure, but also
by the constrictor or dilator action of the nerve fibres which
regulate the tone of the branches of the hepatic artery and the
portal vein in the liver. According to certain experiments of
E. Cavazzani and G-. Manca (1894-95), the vaso-constrictor fibres
of the branches of the portal come directly from the splanchnics
and the caeliac plexus, and the vaso-dilators mainly from the
vagi. The branches of the hepatic artery, on the contrary, receive
their vaso- constrictors mainly from the vagi, their vaso-dilators
mainly from the caeliac plexus. During asphyxia, phenomena of
dilatation are mainly obtained in the branches of the hepatic
artery, and phenomena of constriction in those of the portal vein.
Electrical stimulation of the vagi and branches of the caeliac
142 PHYSIOLOGY CHAP.
plexus produces opposite phenomena in the region of the portal
vein and in that of the hepatic artery ; while the former contracts
with excitation of the plexus, and expands with stimulation of
the vagus, the latter contracts on exciting the vagus, and enlarges
with excitation of the caeliac plexus. While section of the vagus
abolishes the effect of asphyxia on the artery, it does not affect its
action on the branches of the portal vein.
Although the influence of these changes in the tone of the
venous and arterial hepatic vessels upon the process of -biliary
secretion was not studied by the above workers, it may on analogy
be taken as highly probable that vascular constriction (particularly
of the portal branches) determines a slowing, and dilatation an
acceleration, of the flow of bile.
While there can be no doubt that the secretory activity of the
liver, like that of the other glandular organs, is indirectly affected
by the nerves which regulate vascular tonicity, there are at
present no data to demonstrate the existence of secretory nerves
to the liver, exerting a direct control upon the secretion of bile.
All the nerves to the liver can be divided without causing arrest
of the biliary secretion ; all branches of the nerves to the liver can
be excited one after the other, without causing a flow of bile, if
the secretion was suspended, or accelerating it if already taking
place (Heidenhain).
Falloise (1903) found on dogs that application of hydrochloric
acid to the mucous membrane of the duodenum, or upper part of
the small intestine, provoked increase of the biliary secretion. At
the same time it may be questioned whether this is a true reflex,
as asserted by Fleig. Falloise interprets the phenomenon by
admitting the transformation of pro-secretin into secretin, which
on reaching the liver increases the formation of bile by local
stimulation. In reality this pretended cholagogic action is
abolished neither by narcotics, nor by strong doses of atropine.
On the other hand, Henri and Portier (1902) observed that the
injection of secretin caused an acceleration of biliary secretion.
The same objections apply here in regard to the " secretin hypo-
thesis " as were raised for the pancreatic and intestinal secretions.
Friedlander and Barisch (1860) connected the hepatic duct of
the guinea-pig with a vertical glass tube, so as to determine the
point to which pressure can be raised in the bile ducts. They
saw that the bile ascends in the glass tube with a gradually
decreasing velocity, which ceases when it has reached a certain
height, varying from 184-212 mm. Since the pressure in the
portal vein, according to the determinations made by von Basch
on dogs, varies from 7-16 mm. Hg, corresponding to a column of
bile about 191-208 mm., the pressure under which bile is secreted
is always more or less higher than the pressure at which the blood
circulates in the portal system. This was confirmed by comparison
ii EXTEBNAL DIGESTIVE SECKETIONS 143
of the two pressures, measured simultaneously by Heidenhain on
dogs. This phenomenon, perfectly analogous with that which
Ludwig found for the salivary secretion, shows that the bile
secretion cannot, even if it fluctuates with the variations in the
circulatory conditions of the liver, be regarded as an effect of
simple filtration through the vessel walls, but must depend on the
activity of the hepatic secretory cells.
In proportion as the elimination of bile by the excretory duct
is obstructed, it is reabsorbed, and the phenomena of jaundice
appear. The skin and conjunctiva of the eye become yellow,
which is the external sign of ckolaemia, or admixture of bile with
blood. The bile is not absorbed directly by the blood-vessels of
the liver, but by the lymphatics, which convey it to the thoracic
duct, whence it is poured out into the blood torrent. This fact,
already surmised by Sanders in 1795, was demonstrated experi-
mentally by von Fleischl in 1872. Harley has recently shown
that if after ligation of the choledochus the thoracic duct is also
tied in a dog, there will for 17 days be no constituents of bile,
either in the blood or the urine, and no external sign of jaundice.
In this case, all the bile collects in the gall-bladder, and along the
thoracic duct and its roots in the liver.
XXI. The bile collected from the gall-bladder of dead bodies,
or obtained by fistula from man and other animals, is a mixture
of the secretion from the hepatic cells, and that of the epithelia
which line the bile ducts and gall-bladder. Along the excretory
ducts, the products of the hepatic cells are mingled with mucus
and cells in process of disintegration, which make it more dense,
more viscid, and less limpid and transparent. The reaction is
alkaline from the carbonate and phosphate of sodium, the colour
varies in different animals (golden-yellow in carnivora, grass-green
in herbivora, greenish-yellow in man), the taste is bitter. That
of man, exclusive of mucus, contains O'5-l per cent solids, of
which 0'7-0'8 per cent are mineral. Within the gall-bladder it
condenses from absorption of water till the solids amount to
16-17 per cent with specific gravity 1 -010-1-040.
The specific constituents of bile are the bile acids and
pigments.
The Hie acids are never found in the free state, but always in
the form .of sodium salts (potassium salts in sea fishes). They are
acids containing nitrogen, and are composed of cholalic acid (or
related acids), glycine and taurine. It is remarkable that the
quantity of cholalic acid never varies sensibly in animals of the
same species. On the other hand, in different biles the relative
amount of glycocholic and taurocholic acid may vary, although
the former always exceeds the latter in quantity. Besides
cholalic acid, according to Schotten and Lassar Cohn, human bile
contains two other related acids — fellinic and chole'inic acid, which
144
PHYSIOLOGY
CHAP.
last is constantly present, and according to Lutschinoff forms the
fundamental acid of ox -bile.
Chemists distinguish a numerous series of bile pigments, which
represent various degrees of oxidation in the same molecular
aggregate. Under physiological conditions only two of these
pigments appear in the bile, the red or bilirubin, and the green or
biliverdin. The first is less oxidised, and represents the mother
substance of all the other pigments, and it is readily transformed
into the second by simple exposure to air (Maly). Biliverdin
is, vice versa, converted into bilirubin by a process of reduction.
By action of hydrogen in the nascent state these pigments are
converted into hydrobilirubin, which, as we shall see, occurs
continually in the intestine ; a certain amount of hydrobilirubin
can, however, be found even in human bile. Bilirubin and
biliverdin usually co-exist in the bile, but the first largely
predominates in the bile of carnivora, the second in that of
herbivora, while the one or the other predominates in that of man
(omnivora) according as the food is mainly animal or vegetable.
Hammarsten's analysis of the chemical composition of human
bile, taken from the gall-bladder of persons operated on for
cholelithiasis, and from patients with a fistula of the gall-bladder,
give the following results : —
In 100 Parts.
Bile from the
Bile from the Gall-
Fistula.
Bladder.
Water
96-5 -98-3
82-96-83-98
Solid substances
3-5 - 17
17-03-16-02
Mucin and pigments
0-27 - 0-9
4-19- 4-43
Alkaline bile salts .
1-8 - 0-26
9-69- 872
Glychocholic acid
1-6 - 0-2
6-95- 6-78
Taurocholic acid
0-05 - 0-3
274- 1-93
Fatty acids (from soaps)
0-024- 0-14
1-11- 1-05
Cholesterin
0-04 - 0-16
0-98- 0-87
Lecithin .
0-06 - 0-17
0-22- 0-14
Fat .
0-06 - O'lO
0-19- 0-15
Soluble salts
0-7 - 0-8
0-28- 0-3
Insoluble salts
0-02 - 0-05
0-22- 0-23
As shown by this table, besides the bile salts and pigments
(which are the specific substances of bile), fats, soaps, cholesterol,
and lecithin are never absent; these substances are compounds
present in other tissues and secretions. In the bile of certain
animals there is also a diastatic enzyme; this is probably not
hepatic in origin, but is absorbed from the pancreas, and eliminated
by the liver in the bile. Choline and glycero-phosphoric acid are
also found, which are probably decomposition products of lecithin.
ii EXTERNAL DIGESTIVE SECRETIONS 145
•
Normally the bile also contains urea, particularly that of the
cartilaginous fishes. As regards mineral substances, sulphates are
almost entirely absent from the bile, which shows traces of copper,
zinc, and particularly of iron, in an amount that varies with the
nature of the food. According to Novi, the quantity of iron is
less in dogs fed with bread, greatest in a flesh diet ; according to
Dastre, the iron content of the bile varies even with a uniform
diet, according as the haematopoietic or the haematolytic processes
predominate. The iron introduced in a medicinal form is also,
according to some authors, retained by the liver and eliminated in
the bile (Novi, Kunkel), this being disputed by others (Hamburger,
Gottlieb, and Anselm).
According to Craciunu (1901), the composition of bile varies
with age. The bile of young animals up to three years old
contains less water and more solids than that of adults (9'8-10'5
per cent against 8-8*1 per cent solids). In young animals there
are also more mucin, more mineral salts, cholesterol, and bile salts ;
in adult animals more fats and lecithin.
PettenJcofer's Reaction is used to detect the presence of bile acids. The
acids or fluids containing them are treated with a little 25 per cent solution
of cane sugar, and sulphuric acid is carefully added, so that it forms a layer
under the solution. A reddish-purple colour appears at the junction of the
liquids, and also where it comes into contact with any froth at the surface.
The presence of nitrates may disturb the reaction.
In testing for bile acids in the blood and urine, the following is the best
method : —
Dilute the blood with two volumes of water, and coagulate the proteins by
heating with a few drops of acetic acid. Filter off the coagulurn and
evaporate the solution on a water-bath. Extract the residue with absolute
alcohol which dissolves the bile salts, while the proteins remain undissolved,
and evaporate off the alcohol. Dissolve the residue in water containing a
little sugar, and add sulphuric acid diluted with an equal volume of water
and cooled. On gently warming, the originally cloudy solution clears up, and
turns successively orange, yellow, red, and purple. To detect bile acids in
urine, it is only necessary to evaporate it to dryness, then extract with
alcohol, and proceed as described for blood.
A more convenient method has recently been introduced, based 011 the
fact that the presence of bile acids enormously increases the surface tension
of urine. We shall give this method in detail when discussing the katabolic
products of urine.
Gmelin's test for bile pigments. Pour 5 c.c. nitric, with a drop of nitrous
acid, into a watch-glass, then carefully introduce the fluid to be examined by
a pipette, without allowing it to mix with the reagent. At the point of
contact of the two fluids, rings of different colours are formed, which are
green, blue, violet, red, and yellow, as they spread from the centre to the
periphery. Each colour represents a successive stage in the oxidation of
the bile pigment.
The tests for cholesterol are also interesting. Cholesterol is the chief
constituent of the calculi formed in the bile-ducts and gall-bladder, which
give rise to hepatic colic.
1. On adding a few drops of sulphuric acid diluted with one-fifth its
volume of water to some cholesterol in a porcelain capsule, a carmine-red
colour results (Moleschott).
VOL. II L
146 PHYSIOLOGY CHAP.
i
2. On adding a few drops of a mixture of 2-3 volumes concentrated HCL,
and 1 volume of dilute perchloride of iron to some cholesterol, and evaporat-
ing, a residue is obtained, which is at first red-violet in colour, afterwards
blue-violet (U. Schiff).
XXII. Far more is known of the origin of Hie salts and
pigments (though the data are still incomplete) than of the
formation of the other secretory products which are poured into
the intestinal tube.
The fundamental question is whether these specific constituents
of the bile are pre-formed in the blood, the liver only having the
task of eliminating them, as the kidneys eliminate the constituents
of urine, or whether they are exclusively formed in the liver, i.e.
are they specific products by external secretion of the hepatic
cells, and not the products by internal secretion of many or all
the tissues of the body. The first theory (already adumbrated
by Aristotle and Galen) was upheld in more recent times by
Morgagni, van Swieten, and Glisson ; the second by Sanders, Job.
Miiller, Kunde, Moleschott. In accordance with their opposite
points of view, the former admit the possibilities of a Jiaematogenous
as distinct from a hepatogenous jaundice] the latter regard
cholaemia and jaundice as invariably due to the reabsorption of
the bile formed in the liver, i.e. as being essentially hepatic in
origin.
Till quite lately, the arguments in favour of this last theory
were not adequate to solve the question : —
(a) The blood that supplies the liver contains (it was said)
neither acids nor bile pigments; these must therefore be formed
in the liver. But (as Baldi pointed out) this argument loses all
value if we reflect that many kilos, of blood pass through the
liver in the 24 hours, and that the amount of biliary products
the blood must contain as the equivalent of what the liver secretes
during the same period is excessively small, certainly less than
3 grms. per cent, and therefore not to be detected by the
chemical means at our disposal.
(Z>) After extirpation of the liver in the frog (J. Miiller, Kunde,
Moleschott), the bile constituents do not accumulate in the blood,
as they do after tying the bile-duct. The frogs in which
Moleschott excised the liver lived 15 to 21 days, without any appear-
ance of cholaemia or jaundice. To this Baldi replies that the
metabolism of frogs is so sluggish that enough bile would not
collect in a few days in the blood or urine, to be detected chemi-
cally. In fact, when Ley den tied the bile-duct in frogs there
was no sign of jaundice after 14 days. Kobner, in Heidenhain's
laboratory, did detect bile acids in the frog's urine, after ligation
of the bile-duct. But even if this argument proves that the
liver forms bile, it does not exclude the possibility of its formation
by other tissues also.
ii EXTERNAL DIGESTIVE SECRETIONS 147
(c) Secretion of bile ceases in cases of fatty degeneration of the
liver, yet there is no jaundice. Frerichs cites a clinical case in
which no bile salts were found in the urine. But Baldi, on
poisoning dogs with a fistula of the gall-bladder by small doses
of phosphorus which produced fatty degeneration of the liver,
observed that bile still flowed from the liver up to a few days
before the death of the animal. When, owing to catarrh of the
bile-ducts, the flow from the fistula ceased, bile salts were found
to be present in the urine. He noted, moreover, that after long
abstinence the hepatic cells of frogs became atrophied, while the
gall-bladder swelled, owing to the enormous accumulation of bile,
till it equalled or exceeded the volume of the liver. He further
observed that transfusion of ox-blood into dogs with fistula of the
gall-bladder not only increased the flow of bile freely given off by
the fistula, but caused the passage into the urine of bile acids and
pigments. From this it is legitimate to conclude that bile is not
an exclusively hepatic formation, and that the heterogeneous blood
transfused gives rise by decomposition of haemoglobin (as held by
Landois) to the bile pigments, and may possibly, by decomposition
of protein, account for the formation of bile acids.
(d) It is impossible, either during abstinence or in digestion,
to demonstrate the presence of bile constituents in normal hepatic
tissue by micro-chemical means. The varying aspect of the hepatic
cells in these two periods (which we shall study elsewhere) seems
to be exclusively connected with the formation of glycogen (Cl.
Bernard), and not with the formation of bile. This fact seems
to favour the ancient doctrine of the diffuse formation of bile,
rather than the theory which regards it as the exclusive secretion
of the liver cells.
None of these data, as can be seen, gives a decisive answer in
regard to the exclusively hepatic origin of the specific products of
bile. Other more recent work, however, leaves no doubt as to
this point. We may summarise the most cogent and conclusive
arguments : —
(a) If bile, like urine, were the excretory product of different
tissues, its nitrogen and sulphur content would vary in proportion
to the total protein consumption of the body. Kunkel (1870)
and Spiro (1880), on the contrary, show on dogs with fistula of the
gall-bladder that only a small part of the nitrogen and sulphur
from the proteins of the food are eliminated with the bile, and
that this quantity does not increase proportionately with the
amount of protein ingested. When the amount of protein intro-
duced as food is increased eight times, the amount of nitrogen
and sulphur in the bile is only doubled. Barbera (1896) showed
that this increase of nitrogen in the bile is also seen after the
ingestion of fats. It does not therefore depend on the greater
quantity of nitrogen circulating in the blood, but solely on the
148 PHYSIOLOGY CHAP.
fact that both proteins and fats excite the hepatic cells and
accelerate the secretory function.
(/?) Stern's experiment on pigeons (1885) is more decisive.
After total occlusion of the liver in these birds, by ligation of
all the vessels that enter or leave it, including the bile-duct,
urinary secretion is arrested, and bile pigments do not appear
either in the blood serum or in extracts of the tissues, even with
Gmelin's highly sensitive test. When, on the other hand, Stern
confined himself to occluding the bile-duct only, the pigments
appeared in the urine after an hour and a half, and after five
hours they could be detected in the blood serum. This shows
plainly that the bile pigments in circulating blood are formed
exclusively in the liver.
(y) The experiments of Minkowski and Naunyn (1888) on
geese are no less important. They destroyed a considerable pro-
portion of the erythrocytes of two geese, in one of which the liver
had been excised by inhalations of arseniuretted hydrogen, and
observed that after half an hour the goose with a liver gave off
urine containing biliverdin and bile acids, while the goose with
no liver gave urine which contained abundance of haemoglobin
with no trace of pigments or bile acids. On then removing the
liver of the first goose, and occluding all the vessels, including
the bile-ducts, they noted after some time that the serum of the
blood contained neither bile pigments nor bile acids. These
experiments are complementary to those of Stern, showing that
not only the bile pigments but also the bile acids have an
exclusively hepatic origin.
(5) The same interpretation holds for the experiments per-
formed by v. Fleischl with Ludwig on dogs. Having tied the bile-
duct and inserted a fistula in the thoracic duct, he showed that the
lymph that escaped from the fistula contained the constituents of
bile, which are absent when the bile-ducts are not occluded. On
tying both the bile-duct and the thoracic duct on the other dog
at the same moment, he saw that the latter swelled from the
accumulation of lymph, while no trace of bile salts could be
detected in the blood. This result, which was subsequently con-
firmed by Harley, shows not only that bile is exclusively produced
by the liver, but also that after occlusion of the bile-ducts it is
reabsorbed exclusively by the lymphatic paths to the thoracic
duct. Both these experiments of Fleischl and those of Minkowski
and Naunyn with inhalations of arseniuretted hydrogen show
that the haematic or extra-hepatic origin of jaundice can, under
no circumstances, be admitted, even where the latter is confined
to the accumulation of the bile pigments in the blood. The
presence of bile pigments in the urine of a patient invariably
denotes reabsorption — in part at least — of the bile by the
lymphatics of the liver. Occlusion of the larger bile-passages is
ii EXTEKNAL DIGESTIVE SECKETIONS 149
not essential to this absorption. A slight obstruction to the out-
flow of bile in any of the primary bile -ducts suffices to cause
overflow of the secretion stagnating in these passages into the
lymphatics, and thence into the blood.
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150 PHYSIOLOGY CHAP.
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ii EXTERNAL DIGESTIVE SECRETIONS 151
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1910, xxvi. 169.
J. L. TUCKETT. On the Production of Glycosuria in Relation to the Activity of
the Pancreas. Journ. of Physiol., 1910-11, xli. 88.
MECHANICS AND CHEMISTRY OF DIGESTION IN THE MOUTH
AND STOMACH
CONTENTS. — 1. Historical. 2. Mastication, insalivation, formation of aliment-
ary bolus, and saccharificatiou of starch. 3. Mechanism of deglutition. 4. Innerva-
tion. 5. Artificial digestion in vitro to determine action of gastric juice on different
food-stuffs. 6. Influence of spleen on gastric digestion. 7. Natural digestion
in the stomach. 8. Effects of total gastrotomy. 9. Active movements of
stomach in gastric digestion. 10. Mechanism of vomiting. 11. Peripheral and
central innervation of stomach. Bibliography.
THE term " Digestion " usually denotes the complex of mechanical
and chemical changes effected in the food -stuffs by the muscular
tissue of the gastro-iutestinal canal and by the secretions of the
glands discussed in the last chapter. By these changes the food-
stuffs are reduced to the form necessary for their rapid absorption,
assimilation, and transference to the blood stream.
By " food -stuffs" in the widest sense, we mean all those
substances which are normally contained in the blood plasma,
or can readily be converted into the same, and which do
not represent the end-products (or metabolites) of tissue
consumption, destined as such to be eliminated from the body.
A perfect diet must therefore contain («) protein ; (5) fats ; (c)
carbohydrates ; (d) water ; (e) various salts, the bases of which
are Na, K, Ca, Mg, Fe, and hydrochloric, sulphuric, and phosphoric
acid. The three groups of organic substances (proteins, fats, carbo-
hydrates) are oxidisable, i.e. they contain potential energy which
is greater or less in proportion to their capacity for oxygen ; the
mineral constituents (water find salts), on the contrary, are not
capable of being oxidised, and are therefore useless as sources of
energy, and merely fulfil the role of common solvent, or passive
material of construction. We shall discuss the physiological
classification of foods, according to the functions of each group of
substances (which is fundamental to the theory of nutrition"),
elsewhere, when we consider metabolism, i.e. the material
exchanges of the body as a whole.
Of the oxidisable organic substances on which we subsist, sugar
152
CH. in DIGESTION IN THE MOUTH AND STOMACH 153
and certain proteins only are soluble in water ; starch, coagulated
protein (e.g. meat and boiled egg-white), and fats are insoluble.
The mechanical and chemical object of digestion is to modify
these substances, and to render them soluble and readily diffusible.
Mineral constituents being soluble need undergo no change in
the gastro-intestinal canal to fit them for entering the blood.
The mechanism of digestion is so bound up with its chemistry,
that to treat them separately seems to us no less grave an error
than to discuss the theory of nutrition before that of digestion.
I. The first series of methodical experiments on Digestion were
those of Eeaumur (1683-1757). The Accadeniici del Cimento,
disciples of Galileo, and founders of the iatro-mechanical school,
had previously experimented on ravens, and seen that the stomach
of these birds is capable with its powerful muscles of pulverising
the hardest bodies, which lent support to the view that digestion
consisted essentially in trituration (Borelli, Pitcairn, Boerhaave).
It was known, however, that in man and mammals, where the
digestive powers are very great, the stomach has such thin walls
that digestion can only be conceived as the effect of chemical
solvents (Wepfer, Viridet, Valisnieri). In order to decide between
the mechanical and the chemical theory, Eeaumur carried out a
series of experiments in which ostriches were made to swallow
perforated metal tubes containing food. The first results were
negative or very doubtful, but his later work on birds of prey,
which have a membranous stomach, yielded conclusive results, and
convinced him of the chemical character of the forces that, in the
majority of cases, effect digestion. When, however, he attempted
to digest in vitro by means of gastric juice obtained from sponges
which his tame buzzard was made to swallow and then regurgitate,
after which the fluid which the sponges had imbibed was squeezed
out, his results were negative, and he gave up the experiments.
Nearly half a century later the same experiments were taken
up again by Spallanzani (1783) with complete success, and he
confirmed the discovery of Eeaumur, and further demonstrated
the possibility of artificial digestion in vitro, without the inter-
vention of mechanical factors. He suspected the presence in the
gastric juice of a ferment of neutral reaction, as discovered by
Schwann in 1837, a ferment on which the solvent power of the
gastric juice depends. Lastly he made a most important dis-
covery from the standpoint of medicine and hygiene, i.e. the
non-putrefaction of gastric juice, to which is due its sterilising
action on the foods introduced; this being possibly, as we shall
see, the most important function of the acid secretion of the
stomach.
The Congress convened at Paris in 1823 by the Academie des
Sciences with the object " de determiner par une serie d'experiences
chimiques et physiologiques, quels sont les phenomenes qui se
154 PHYSIOLOGY CHAP.
suceedent dans les organes digestifs durant 1'acte de digestion," led
to the publication of two important monographs, one by Leuret and
Lassaigne (1825), the other by Tiedemann and Gmelin (1826), in
which the entire process of digestion was for the first time
submitted to an experimental criterion. The work of the two
German authorities in particular must be regarded as the starting-
point of subsequent experimental researches, since they established
the foundations on which the whole of the modern doctrine of
digestion rests.
In collecting the gastric juice, Tiedemann and Gmelin intro-
duced a modification of the method pursued by Reaumur and
Spallanzani, since they caused dogs to swallow insoluble bodies in
order to stimulate the walls of the stomach. They then killed the
animals, collected the juice secreted, and studied its solvent action
on food in vitro. A few years later (1833) Beaumont published
his experiments on the Canadian trapper, Alexis St. Martin, who,
in consequence of an accident, had a large gastric fistula, which
made him a convenient subject for the study of the phenomena of
natural digestion. And shortly after (1834) Eberle published his
discovery of artificial gastric juice obtained from extract of mucous
membrane, with which numerous series of artificial digestions in
vitro were carried out by himself, by Job. Miiller, Schwann,
Wasmann, Vogel, Valentin, etc. This return to Spallanzani's
method indicates a marked progress in the positive knowledge of
the nature and properties of the digestive process.
Among the more complete monographs on digestion, of special
historical interest, are those of Blondlot (1843), Frerichs (1846),
and Bidder and Schmidt (1852).
II. The Digestive System, which is a canal extending from
the mouth to the anus, has on an average a length of about nine
metres. The part that lies in the head, neck, and thorax measures
from the mouth to the cardiac orifice of the stomach some 38 to
46 cm. ; the remainder, situated between the abdomen and the
pelvis, is almost twenty times as long. The former includes the
mouth, the pharynx, and the oesophagus ; the latter the stomach,
the small intestine, and the large intestine. This anatomical
division clearly indicates the lines we must follow in studying the
mechanical and chemical changes in the food-stuffs introduced into
the digestive canal.
The first 'secretion which the food encounters is the saliva
poured into the buccal cavity, in a daily quantity (according to
Bidder and Schmidt) of more than 1500 c.c. Prima digestio fit in
ore, as the ancients phrased it. At first sight it appears as if the
saliva, secreted in such abundance, must have a highly important
chemical function. Everything, on the contrary, indicates that
the operations effected on the food in the mouth are mainly of a
mechanical character,
in DIGESTION IN THE MOUTH AND STOMACH 155
Fluids, whether taken into the mouth by sucking or drinking
(i.e. imbibed or gulped down), are immediately swallowed; solids,
on the contrary, are masticated before swallowing.
If a fluid is taken up by imbibing, this is effected by the
negative pressure which is produced in the buccal cavity during
an inspiration, provided the communication between the pharynx
and the nasal fossae is closed by elevation of the palate. In
order that the liquid shall be imbibed, the edges of the lips
must be applied to the edge of the glass and to the surface of
the fluid. When a fluid is gulped down, the mouth is half-open,
and the lower lip makes a funnel which conducts the fluid to
the mouth.
Sucking, by which the infant draws its nourishment from the
glands of the breast, is effected by the vacuum produced in the
mouth by depression of the roof, retraction of the tongue towards
the throat, and sometimes by dropping of the lower jaw (Auerbach),
while the lips completely enclose the nipple. The negative
pressure which determines the flow of milk into the buccal cavity
oscillates, according to Herz, between 3 and 10 mm. Hg ; this last
figure, however, seems to us exaggerated.
Mastication of solid foods is accomplished by the voluntary
movements of the lower against the upper jaw, assisted by the
movements of the tongue, by which the food is pushed between
the two rows of teeth, which are the passive instruments of
trituration ; the canines and incisors serve particularly for pulling
and tearing, the molars for biting up the food.
The teeth make their appearance in the first two years of
childhood — these being the milk teeth destined to be gradually
replaced by the permanent teeth from the seventh year onwards.
The milk teeth are 20 in number : 8 incisors, 4 canines, 8 molars ;
the -permanent teeth are usually 32 : 8 incisors, 4 canines, 8 pre-
molars, and 12 molars. Comparison of the form of the teeth in
man and in the carnivora and herbivora, gives a plain anatomical
proof that a mixed diet is that best adapted to the nature of man.
This is confirmed by the length of his intestine, which holds the
mean between that of herbivora, which is much longer, and of
carnivora, which is. much shorter.
Elevation of the lower jaw is effected by means of the temporal,
masseter and internal pterygoid muscles ; its depression, by gravity,
and by the action of the anterior surface of the digastric, mylo-
and genio-hyoid muscles, and the platysma ; the forward movement
by the simultaneous action of the external pterygoids; the
retraction by the simultaneous movement of the internal ptery-
goids ; and the sideway movements by the alternate action of the
external pterygoids on both sides (Fig. 52, A and B).
The masticatory movement is regulated by the tactile sensibility
of the teeth and the buccal mucous membrane, and by the
156
PHYSIOLOGY
CHAP.
muscular sense of the muscles that come into play ; it is activated
by the motor roots of the third branch of the trigeminals, aided by
the hypoglossal and facial nerves. The immediate common centre
of the masticatory movements, according to Schroder van der
Kolk, lies in the medulla oblongata; this view is not, however,
supported by any definite anatomical evidence. Since the move-
ment is complex and voluntary, its centre probably lies in the so-
called motor zone of the cerebral cortex. In fact, the electrical
excitation of a circumscribed area in the lower lateral part of the
cortex of the anterior lobe of the brain in rabbits readily produces
FIG. 52.— A, internal pterygoid muscles viewed from outside. (G. D. Thane.) The masseter
muscle, greater part of zygomatic arch, temporal muscle with coronoid process, and a large
part of the ramus of the jaw have been removed ; 1, external pterygoid, the figure is placed
on the lower head ; 2, internal pterygoid. B, lower part of skull and face to show attach-
I III' Joint Separated by till- UILt-|-<u in uun liuiu-ixilblicl£c , ' , ,^t> MII-H^.-M.^ im-uii , i, ji-it uin i Mm
pterygoid muscle ; 1', lower part of same muscle, on right side, the middle is cut away to
show external pterygoid ; 2, lower head of external pterygoid ; 2', upper head of the muscle,
attached in part to the inter-articular disc ; 3, origin of mylo-hyoid and genio-glossus muscles
from the mental spines ; 4, origin of mylo-hyoid ; 5, attachment of anterior belly of digastric ;
6, 6, masseter muscles.
movements resembling those of mastication. The centrifugal
paths from this area lead through the corona radiata to the median
segment of the internal capsule, and may be followed into the
anterior mesial part of the cerebral peduncle.
Simultaneously with mastication comes the insalivation of the
food, by which its particles are worked into a mass, which, when
carried to the back of the tongue, becomes rounded and is called
the bolus. The movements of the tongue, besides shifting the
food to and fro between the rows of teeth, help in shaping the
bolus from the fragments already chewed and insalivated.
According to Gaudenz (1901) a mouthful suited for mastication
normally has a volume of about 5 c.c. Its weight depends on the
specific gravity of the foods. Such a mouthful in a normal man
in DIGESTION IN THE MOUTH AND STOMACH 157
is sufficiently chewed in half a minute to determine the reflex of
deglutition, independent of the nature of the food. The masticated
pulp contains a certain quantity of coarse particles from 7-12 mm.
in diameter, according to the nature of the food ; the smallest
particles are only O'Ol mm. in diameter. Pieces larger than
12 mm. in diameter are retained in the mouth during deglutition
of the pulp; and subjected to fresh trituration. As a rule vegetable
foods are better masticated than animal matters.
The most important function of saliva is certainly the prepara-
tion of a bolus from the masticated food, which is then ready for
deglutition. Saliva has no chemical action on the greater part of
the food-stuffs, and is limited to the conversion of the starch into
dextrin and sugar, with absorption of water. This action takes
place rapidly on cooked starch, very slowly upon raw, and is due
exclusively to the ptyalin, which acts in a slightly alkaline, or
even in a faintly acid medium, so that its action must cease in the
stomach, as soon as the acidity of the gastric juice exceeds that of
0'5 per cent HC1. The saccharifying power of the enzyme is less
when it is made to act on a large amount of starch ; moreover, it
is easily exhausted.
Cannon and Day (1903) studied salivary digestion in the
stomach of the cat by isolating the different parts of the stomach
with ligatures, at a given time after the ingestion of food, and
testing them singly for the sugar content. They found that in
the fundus, the contents of which do not mix for a long time with
those of the pyloric region in the cat, the saliva produces a con-
spicuous formation of sugar from the starch, without disturbance
by the hydrochloric acid of the gastric juice.
The amylolytic or diastatic action of the saliva is accomplished
in stages, i.e. it passes through certain intermediate products.
The first stage of starch conversion is that of amidulin (Nasse) or
soluble starch, which turns blue with iodine like insoluble starch ;
amidulin is then transformed into erythrodextrin (Briicke), which
turns deep red with iodine ; the erythrodextrin changes into
achroodextrin (Briicke), which no longer stains with iodine ; lastly,
a portion of the achroodextrin is converted into maltose (von
Mering and Musculus), and a small portion into glucose
(Zimmermann), which give the ordinary sugar reactions.
Besides maltose, there is always a certain amount of dextrin
and unaltered starch in the end-products of the amylolytic action
of saliva, as exerted by ptyalin on starch. According to Sheridan
Lea, 3 '41 2 grms. of boiled starch, left to digest for a number of
hours with 100 c.c. of saliva, yield 2'83S grms. of maltose, and
0'505 grin, of dextrin. On the other hand, it is certain that a
small quantity of saliva suffices to saccharify a large amount of
starch (Briicke).
Clemm (1902) showed that simple salivary digestion con-
158 PHYSIOLOGY CHAP.
tinned for three days at body temperature, produced sugar,
both from animal starch (glycogen) and from vegetable starch
(potato) ; the whole of the maltose was split into two molecules of
glucose.
Surprising as is the readiness with which ptyalin acts upon
cooked starch, the time of its action is very short, and incom-
parably less in intensity than that of the analogous enzyme of
pancreatic juice.
Eecent researches prove that salivary digestion has a much
greater importance than was formerly supposed.
J. Miiller (1901), e.g., found that saliva converts 50-70 per cent
and even more of the alimentary starches into soluble products
closely related to maltose. In cases of weak acid secretions in the
stomach, only very minute fractions of starch, as a rule, remain
undissolved. The saccharification of starch is therefore most
intense at the commencement of gastric digestion. Gaudenz
(1901), too, found that in the ingestion of starchy foods, such an
amount of saliva was secreted even after half a minute that it
induces a peculiarly energetic process of saccharification, and is
capable of dissolving large quantities of vegetable foods like
macaroni, potatoes, turnips, etc., while animal foods are only
dissolved to the extent in which they contain substances soluble
in water.
The saliva of carnivora, although it is secreted in great
quantities, is entirely destitute of ptyalin, as might be expected
from teleological considerations. The saliva of infants, up to a
year old, is also lacking in ptyalin, and therefore in diastatic
properties (Schiff and others). This is the best proof that the
principal function of the saliva is mechanical, i.e. formation of the
bolus. It must, however, be added that saliva by its alkalinity
also serves to protect the teeth from the corrosive action of acids,
which are readily formed in the mouth by the fermentation and
decomposition of alimentary residues. One argument in favour of
this theory of Bunge is the fact that Cetacea that live in water are
entirely destitute of salivary glands, which are rudimentary in the
Pinnipeda. The emulsifying action of saliva on fats claimed by
some authorities (Colin, Longet, Corona, Ellenberger, Hofmeister)
is due to the mucin which it contains. According to others,
saliva promotes gastric secretion when it reaches the stomach, by
its alkalinity (Strieker) ; but this fact is not conspicuous or
constant enough to render it of importance. Dogs are apparently
none the worse for the extirpation of all the salivary glands, and
only require to drink more frequently than usual during their
meals (Fehr, 1862).
III. The formation of the bolus is succeeded by the act of
Deglutition, which carries it from the mouth to the stomach,
through the pharynx and oesophagus. The analysis of the
in DIGESTION IN THE MOUTH AND STOMACH 159
mechanism of this act is one of the most difficult problems :
•" difficillima -particula physiologiae," as Haller termed it.
Magendie (1808-13) was undoubtedly the one among modern
physiologists who occupied himself most with this phenomenon,
and his description, by its simplicity and clearness, leaves nothing
to be desired. He was the first to distinguish three stages in
deglutition : the first directed by the will, during which the bolus
passes from the mouth to the isthmus of the fauces ; the second
involuntary, of a reflex character, very rapid and almost con-
vulsive, in which the bolus passes the pharynx and reaches the
upper part of the oesophagus; the third involuntary, very slow,
carrying the bolus into the stomach. The mechanism by which
these three acts are performed is essentially the same ; it consists
in a peristaltic movement by which the bolus is driven onwards
and forwards — in the first period by pressure of the tongue
against the palate, owing to contraction of the longitudinal lingual
and the mylohyoid muscles ; in the second by the contraction of
the constrictors of the pharynx, which surround and constrict the
bolus, carrying it forward, while the larynx and hyoid bone are
elevated, and the passage of the bolus through the aperture of the
glottis is accelerated ; in the third by the progressive contraction
of the circular fibres of the oesophagus, dilated by the pressure at
which the bolus is driven forward by the contraction of the
pharynx.
Many details in Magendie's description are the fruit, not
merely of anatomical, but also of direct physiological, observation.
This explains how his theory came to be generally accepted,
subsequent physiologists only introducing slight modifications and
additions, with the object of completing and perfecting it in
various ways.
In 1880, however, after the work of Kronecker and his pupils
and co-workers, doubt was for the first time cast on this doctrine in
regard to its central concept, viz. that the passage of the bolus from
the mouth to the stomach was effected by a comparatively slow
peristaltic contraction, by which it was driven from section to
section till it reached the stomach. In a paper with Talk, Kronecker
notes that when iced water is drunk, there is a feeling of cold in the
stomach directly after the first gulp, i.e. before peristalsis of the
pharynx and oesophagus can occur. Forensic medicine, again, has
described cases of poisoning by swallowing of corrosive fluids, which
showed on examination that the oesophageal lesions were confined
to certain isolated points, the greater part of the mucous membrane
being uninjured — which would not be the case if the liquid
swallowed were propelled down the tube by peristalsis. Patho-
logical observation further shows that while paralysis of the
oesophagus makes deglutition difficult it does not inhibit it.
Kronecker concluded from these facts that the fluid or semi-
160 PHYSIOLOGY CHAP.
fluid bolus is shot into the stomach by the contraction of the
striated muscles, before peristalsis of the oesophagus can take
place. Manonietric observations show that at the commencement
of the act of deglutition there is a rapid increase of pressure equal
to about 20 cm. water near the base of the tongue, and also in the
gullet, but not in the stomach.
Meltzer performed an interesting series of experiments on
himself, to prove that this increased pressure in the retro-buccal
space at the commencement of deglutition suffices to drive the
bolus rapidly into the stomach. When a sound writh a very light
rubber balloon at one end (see Vol. I. fig. 192, p. 429), and a
recording tambour at the other, is passed down the oesophagus to
various measurable depths, two elevations are marked on the
FIG. 53. — Curves of deglutition obtained from himself by Meltzer, on introducing two separate
sounds into pharynx and oesophagus. F, tracing from pharyngeal sound ; K, tracing from
oesophageal sound, passed 4 em. down the oesophagus ; s, time tracing in seconds. A little
liquid was swallowed at A ; more at B ; a large amount at C.
rotating drum at each act of swallowing, which Kronecker terms
" signals of deglutition " (Schluckmarken) : the first signal appears
immediately after the act, independent of the depth to which the
sound lhas been introduced into the oesophagus ; the second, on
the contrary, appears later in proportion as the sound goes
deeper. On introducing a second sound into the pharynx, and
repeating the above experiment, Kronecker and Meltzer obtained
the curves of Figs. 53 and 54.
The rapid rise of the curve from the pharyngeal sound of
Fig. 53 signals the moment at which the bolus (or liquid mouthful)
shoots down the pharynx, and compresses the balloon. A, B, C
show that the height of the elevation is in proportion with the
amount of fluid swallowed. The oesophageal tambour marks no
rise at A to coincide with that of the pharyngeal tambour, owing
to the small amount of water swallowed ; but at B and C the
passage of the fluid into the oesophagus is clearly signalled by
elevations which coincide with those of the pharynx. All three
in DIGESTION IN THE MOUTH AND STOMACH 161
curves then show a second elevation (about 1 sec. after the first),
which depends on the contraction of the constrictors of the
pharynx and oesophagus set up by the passage of the bolus. In
FIG. 54. — Curves of deglutition as in Pig. 53. In A and B the oesophageal sound was passed
12 cm. beyond the opening of the oesophagus ; in C, 16 cm. Less water was swallowed at A
and C than in B.
fact in the tracings of Fig. 54, in which the oesophageal sound
had been introduced farther into the oesophagus, the second rise
occurs much later than the first, which practically coincides
with the pharyngeal signal.
The first signal indicates the rise of pressure in the gullet
VOL. II M
162 PHYSIOLOGY CHAP.
owing to compression from the bolus (solid or liquid), which is driven
through the oesophagus by the forcible contraction of the mylo-
hyoid muscles; the second is due to the successive contraction
of the pharyngeal and oesophageal constrictors of the pharynx
and oesophagus. The increased pressure in the mouth determines
the rapid propulsion of the bolus (fluid, or solid reduced to a
pulp) into the cardia ; the subsequent contraction sweeps away
from the gullet any particles of food that are adherent to its walls,
and overcomes the resistance of the cardia, driving the bolus into
the stomach.
According to Meltzer, the human oesophagus does not contract
by peristalsis, as is usually accepted, but in three sections (the
first being 6, the second 9, the third 6-7 cm. long), each of which
is emptied successively like the several segments of the heart.
When the upper part is in maximal contraction, the lower part
begins to contract, so that the solid bolus (which cannot like
fluids be directly propelled by the thrust of the mylohyoid
muscles) is forced to descend towards the stomach. Meltzer
succeeded in determining the interval between the contraction of
the mylohyoids and of the pharyngeal constrictors (O3 sec.),
between the contraction of the pharyngeal constrictors and that
of the first section of the oesophagus (O9 sec.), between the
contraction of the first and second sections of the oesophagus
(1'8 sec.), between the contraction of the second and third sections
of the oesophagus (3'0 sec.). The sum of these differences
represents 6 sec., which indicates the time necessary for the
bolus to descend from the mouth to the extremity of the
oesophagus, and to overcome the resistance of the cardia and
enter the stomach.
Meltzer confirmed his theory by the simpler method of
auscultation. On listening with the stethoscope in the region of
the stomach, or laterally, at the xiphoid process, a murmur is
almost always heard during the act of deglutition. This coincides
with the moment at which the bolus (or fluid mass) overcomes
the sphincter closure of the cardia and penetrates into the
stomach, which takes place 6-7 sec. after the commencement of
deglutition, and it is therefore called the terminal murmur. In
a much smaller number of cases there is, on the contrary, at the
initial moment of swallowing, a sharp whistling murmur, as if
the liquid swallowed had been shot forcibly and directly into the
stomach. When this sound, which may be called the initial
murmur, is very distinct, the terminal murmur is not heard;
when, on the contrary, it is very dull, the terminal murmur is
clearly heard as well, though faintly. In a small number of
cases no murmur is perceptible on auscultation during the
deglutition of liquids.
Meltzer noted that many persons in whom the initial murmur
in DIGESTION IN THE MOUTH AND STOMACH 163
alone is heard, exhibit atony of the cardia, since during coughing
regurgitation of food from the stomach into the oesophagus readily
occurs ; in those, on the contrary, in whom the cardia is normally
closed, which prevents the bolus from entering the stomach imme-
diately, it remains at the lowest part of the oesophagus, until the
contractile movement of the latter overcomes the resistance of the
cardia, and produces the terminal murmur, which, as seen above,
occurs 6'7 seconds after the commencement of deglutition.
The human cardia is thus normally closed, so that the bolus
(or fluid mass) must remain at the extreme end of the oesophagus,
until the contractile movement of the latter forces it into the
stomach. This closure of the cardia explains why the increment
of pressure determined by Kronecker and Talk in the gullet
during deglutition, does not occur within the stomach.
Kronecker, therefore, differs from Magendie, in not admitting
three successive stages in the act of swallowing. He maintains
that deglutition occurs in one single act in which the bolus (liquid
or pulp) is shot with great velocity and under a relatively high
pressure, as far as the cardia. This, he says, is the fundamental
mechanism of deglutition, in which neither the muscles of the
pharynx nor those of the oesophagus participate, the bolus being
allowed to slide through passively. The whole canal contracts in
successive sections only when the bolus has already reached the
cardia, and this accessory movement is an act complementary to
the normal act of swallowing, which may acquire vital importance
in cases in which a bolus too large or too hard is being swallowed,
and sticks in the oesophagus owing to the insufficient impulse,
producing painful sensations of choking, which have to be removed
by repeated acts of swallowing and drinking of fluid.
The principal factor in the normal act of deglutition is repre-
sented by the muscles of the mylohyoid group, as already recognised
by Magendie, Tourtual, Ludwig. Of this we have direct evidence
in the fact that on dividing the mylohyoid fibres of the motor
branch of the fifth nerve, while the filaments that supply the
digastric muscles are left intact, the animal is no longer able to
swallow, unless it resorts to the expedient of throwing its head
back quickly with the mouth open, so as to jerk the food into the
throat, when the pharyngeal constrictors can come into play
effectively. The muscles innervated by the hypoglossal are also
important to the act of deglutition, which is disturbed by their
resection, owing to the consequent paralysis of the longitudinal
lingual muscle and of the hypoglossal. By the almost simultaneous
contraction of this group of muscles (with which is associated that
of the group of elevator muscles of the hyoid bone and larynx), the
bolus conveyed to the back of the tongue is pressed between tongue
and palate, and driven under strong pressure towards the point of
least resistance, i.e. towards the retro-buccal cavity, — while the
164
PHYSIOLOGY
CHAP.
surface of the root of the tongue, which in the state of rest is
turned backwards, retracts, and carries the epiglottis with it, so
that the glottis closes mechanically. At the same time, the palate
is raised and stretched, not passively, but by the contraction of
the elevator and tensor muscles of the palate, so as to occlude and
separate the nasal from the pharyngo-buccal cavity, with the
assistance of the palato-pharyngeal and the superior constrictor
muscles of the pharynx, which contract and bring forward the
—t
Fio. 55.— Diagram showing position of soft palate, tongue, glottis, pharynx, etc. A, at rest ;
B, during deglutition. (Zaufal.) t, Salpingo-pharyngeal fold ; I, fold of levator palati ;
c, musculo-superior constrictor ; a, azygos uvulae which completes the closure of the nasal
cavity.
pharyngeal walls forming Passavant's swelling, as shown in Fig.
55. This, according to Kronecker, comprises the fundamental
mechanism of deglutition : the rest, as minutely described by
certain authors, is accessory, and serves principally to prevent the
food or drink from taking the wrong path to the glottis or nasal
fossae, and to clear the canal of the food residues, or to drive the
bolus (when it is blocked at the lower end of the oesophagus) into
the stomach, by overcoming the resistance of the cardia.
Another important fact discovered by Kronecker and Meltzer
is that every active movement of swallowing carried out in the
primary segment of the alimentary canal, particularly from the
contraction of the niylohyoid or hypoglossal muscles, produces an
inhibition of the movements of the deeper segments. When, on
in DIGESTION IN THE MOUTH AND STOMACH 165
drinking a fluid, a series of swallowing movements, separated by
an interval of 1-2 seconds, occurs, the subsequent contraction of
the oesophagus is produced only after the final gulp. This is
easily proved by the method of the oesophageal sound, as seen in
the curves of Fig. 56, which also show that the pause which occurs
between the signal of the last act of swallowing, and that of the
subsequent contraction of the oesophagus, is so much longer in
proportion as the number of previous acts of swallowing is greater,
— as if the production of the acts of deglutition gave rise to a
Pro. 56. — Signals of deglutition, recorded by Meltzer from himself, by oesophageal sound intro-
duced as far as the second segment of the oesophagus, i.e. 12 cm. below its commencement.
In curve 1 (top, left-hand) water was only swallowed once, and the second signal occurred
3 sec. after the first. In curve 2 (top, right-hand) fluid was swallowed six times, and the
second signal occurred 4 sec. after the last swallow. In curve 3 eight acts of swallowing were
performed, and the second signal occurred 6 sec. after the last.
delay in the conduction of the excitatory process by which the
peristaltic movement of the oesophagus is developed.
But if this new theory of the mechanism of deglutition pro-
pounded by Kronecker and his school is applicable to fluids and
to substances reduced to a pulp, it is doubtful whether it applies
to soft alimentary boluses, and to solids, which are sometimes
swallowed without, or with imperfect, mastication and salivation.
We are indebted to Cannon and Moser (1898) for the valuable
observations which have solved this doubt and elucidated the act
of deglutition in birds and the higher mammals. They applied
the Rontgen rays to this purpose, bismuth subnitrate being added
to the food to render it opaque. The fluorescent screen employed
was marked at intervals of centimetres with cross lines. A
vibrator marking tenths of a second was interrupted whenever the
shadow cast by the bolus passing through the gullet crossed a line.
166 PHYSIOLOGY CHAP.
By this method the following conclusions were arrived at : —
The mechanism of deglutition varies according to the animal
and the nature of the food swallowed.
In fowls, the movement is slow and peristaltic whatever the
consistence of the food. Any jerking of fluid is obviously
impossible, because the parts surrounding the buccal cavity are
too hard and rigid. Gravity has a predominating importance
over the propulsive power of the mouth. Each time the mouth is
filled with fluid the head is raised, so that the liquid descends by
its own weight into the oesophagus, where it is carried forward by
peristalsis.
In cats, according to these authors, the movement of deglutition
is always peristaltic and much more rapid than in fowls. The
bolus takes 9-12 seconds to reach the stomach. In the upper part
of the oesophagus, fluids move more rapidly than semi-solids. In
the lower or diaphragmatic parts the velocity, for both liquids and
solids, is much less than in the upper parts.
In dogs, the bolus descends to the stomach in 4-5 seconds.
It is always propelled rapidly in the upper part, and more slowly
below. For fluids the rapid movement may be maintained even
in the lower part.
In man and in the horse, fluids are shot into the oesophagus at
a velocity of several decimetres per second, owing to the impulse
from the rapid contraction of the mylohyoid muscles. Solids and
semi-solids are propelled slowly forward throughout the gullet by
peristalsis only, and Kronecker's theory is therefore justified in
regard to the deglutition of liquids and pulp ; but for the degluti-
tion of solids and semi-solids the old doctrine of peristalsis still
holds, although it must be understood in the restricted sense
imposed by the experiments of Kronecker and Meltzer.
The later work of Zwaardemaker and Eyknian, Schreiter,
Kindermann and Kahn has not contributed anything really new
to the subject.
IV. Deglutition is a characteristically reflex act. It is true
that it commences as a voluntary process, but this, which Magendie
regards as the first period of deglutition, during which the bolus
reaches the isthmus of the fauces, has nothing to do with the act
of deglutition proper and may be logically regarded as the final
moment of mastication (Morat and Arloing, 1880). Magendie
devised the following experiment in order to demonstrate the
necessity of the peripheral stimulus — i.e. the bolus or fluid — to
the act of deglutition : —
" Cherchez," he said, " a executer de suite cinq ou six mouve-
ments de deglutition, dans lesquels on avalera la salive contenue
dans la bouche : le premier et merne le second se feront facile-
ment ; le troisieme sera plus difficile, car il ne restera que tres peu
de salive a avaler ; le quatrieme ne pourra etre execute qu'au bout
in DIGESTION IN THE MOUTH AND STOMACH 167
d'un certain temps, quand il sera arrive de nouvelle salive dans
la bouche ; enfin le cinquieme et le sixieme seront impossible,
parcequ'il n'y aura point de salive a avaler."
Since deglutition normally takes place when the bolus or fluid
reaches the isthmus of the fauces, it is evident that the starting-
point of the reflex is represented by the contact of the food with
the sensory nerve-endings distributed to this region. Wassilieff
(Bern, 1888), however, did not succeed in the human throat in
finding any point on the tongue, palate, or posterior and lateral
walls of the pharynx, at which mechanical, chemical, or electrical
stimuli incite the act of swallowing, as the stimulation of the
nasal mucosa incites sneezing, and contact with the glottis
coughing; we must assume that preparatory movements in the
isthmus of the fauces are required in order to excite swallowing in
man, these being absent during experimental excitation when the
throat is kept quiet. In the rabbit, on the contrary, deglutition
is infallibly excited on touching the central part of the anterior
surface of the soft palate, which is some 2-5 mm. broad, and 2 cm.
long, extending from the hard palate halfway along the tonsils.
The least contact in this region produces a complete act of
swallowing. Wassilieff succeeded in evoking fifty in succession
without finding any fatigue of the reflex nervous mechanism.
K. H. Kahn (1903), wTho did much careful work on the reflexes
of deglutition, found that they were excited in the rabbit by
stimulation of the soft palate (trigeminal), in the dog and cat by
stimulating the dorsal surface of the pharynx (glosso-pharyngeal),
in monkeys by stimulation of the upper part of the palatal arch
(trigeminal).
Both in rabbits and in man, anaesthesia of the sensory region
with a concentrated solution of cocaine (10-20 per cent) makes
the swallowing reflex impossible for some time (about a quarter of
an hour). This is the best proof that deglutition is not dependent
on will, as the respiratory movements are under certain conditions.
The sensory fibres to the soft palate, which are the starting-
point of the swallowing reflex in the rabbit, derive from the
trigeminal, the sensibility of the palate to reflexes of deglutition
being permanently abolished after intracranial division of this
nerve.
In 1865 3idder and Blumberg noted that stimulation of the
central end of the superior laryngeal nerve also provokes move-
ments of swallowing. This fact was confirmed by A. Waller and
J. L. Provost in 1870 for both cats and rabbits.
They further found to their surprise that section of both
superior laryngeals produced no marked disturbance of deglutition,
particularly in rabbits, which survived for months after this
operation. On Kronecker's new theory this is not surprising,
since division of the superior laryngeals leaves intact the essential
168 PHYSIOLOGY CHAP-
mechanism of the swallowing reflex, which is effected by way of
the trigeminal.
As regards the glosso-pharyngeal nerve, both Schiff (1867),
and Waller and Prevost found that swallowing was never excited
by its stimulation, and concluded that it does not contribute in
any way (at least in rabbits) to the reflex phenomena of deglu-
tition. Schiff also noted that the division of those nerves in the
same animals produced no disturbance of deglutition. It was left
for Kronecker and Meltzer (1883) to discover that the glosso-
pharyngeal must be regarded as a nerve which reflexly inhibits
the swallowing movements. In order to bring out this fact
Wassilieff performed the following experiment on rabbits. When,
after lateral exposure of the superior laryngeals and glosso-
pharyngeals, the former alone are excited, movements of swallow-
ing are performed; when the latter are simultaneously excited
with weak induction currents the phases of deglutition occur
irregularly and are much delayed ; when, lastly, they are stimu-
lated with strong currents, the effect of the superior laryngeals is
altogether abolished.
The inferior laryngeals or recurrent nerves also contain centri-
petal fibres which are capable of exciting the reflexes of deglutition.
This fact, as already surmised by Valentin (1846), and by Waller
and Prevost (1870), was fully elucidated by Kronecker and
Liischer (1897). They found in a series of experiments on rabbits
that the recurrens sends four branches to the cervical part of the
oesophagus, the lowest of which innervates the upper part of the
thoracic oesophagus also (Fig. 57), and that when the peripheral
trunk of one of these filaments is excited even with weak currents,
a tetanic contraction occurs exclusively in that segment of the
oesophagus in which it ramifies (Fig. 57). When, on the contrary,
the whole trunk of the recurrens is excited, the entire cervical
part of the oesophagus contracts simultaneously. The peristaltic
form of the oesophageal movement that takes place in deglutition
must accordingly depend on a delay in the excitation which
descends to the three branches of the recurrens in succession from
the nerve centre. This agrees with Mosso's earlier and important
observation (1873), to the effect that the peristaltic wave of the
oesophagus is not arrested in swallowing by ligation, nor by section,
nor by extirpation of a quarter of its length ; the wave continues
to be propagated from the upper to the lower segments. It ceases
only after division of the oesophageal nerves. This fact shows
that the peristaltic wave of the oesophagus is not a local pheno-
menon propagated from tract to tract by the muscular coat, as in
the intestine ; but that it results from the nerve impulses that
descend successively by the three branches of the oesophagus from
the nerve centres.
Liischer further noted that stimulation of the central trunk
in DIGESTION IN THE MOUTH AND STOMACH 169
of the recurrens in the rabbit produced the same effect as that
of the superior laryngeal, i.e. a swallowing movement confined
to the upper tract which is innervated by the trigerninal, the
oesophagus being paralysed owing to the occlusion of the centri-
fugal paths contained in the two nerves resected. In morphinised
rabbits, reflex deglutition from the two laryngeals occurs less
readily than in the normal ; sometimes, however, when the
superior laryngeal is out of court, deglutition can be excited by
the inferior laryngeal. After bilateral section of the two inferior
laryngeals, rabbits die in a few days from pneumonia owing to
the blocking of the oesophagus from the paralysis of its muscles.
Fid. 57. — Diagram of the four branches of the recurrens which supply different parts of the
oesophagus in rabbit. (Liischer.) v, vagus ; r, reeurrens ; 1, 2, 3, 4, its brandies ; es,
oesophagus ; tr, trachea ; It, border-line of thorax.
The nerve centres which preside over and co-ordinate the
movements of swallowing lie in the upper part of the medulla
oblongata, for destruction of the brain above the respiratory
centres (more exactly above, and external to, the ali cineraee of
the rhomboidal sinus) does not abolish the movements of deglu-
tition (Wassilieff, Marckwald). We know, on the other hand,
from pathology that the so-called bulbar paralysis produces
disturbance or inhibition of the act of deglutition. Nothing,
however, is known as to the localisation of these centres, on which
depends the co-ordination of the successive movements in the
various tracts (buccal, pharyngeal, oesophageal) of the alimentary
canal.
The centrifugal paths (as may easily be inferred from the
above experiments) lie in the motor portions of the trigeniinal
and hypoglossal nerves for the mylohyoid, hypoglossal, and lingual
170 PHYSIOLOGY CHAP.
muscles ; in the vagi and spinal accessory for the muscles of the
palate, pharynx, and oesophagus.
The cardia belongs by its movements to the oesophagus, its
function being co-ordinated with the swallowing movements in
the latter ; it contracts after the last part of the oesophagus, and
loses its tonicity when the oesophagus is relaxed under the
inhibitory influence of the glosso-pharyngeal nerves.
V. On reaching the stomach the alimentary boluses remain
there for several hours, according to the nature of the food, and
suffer various changes of a chemical character. The importance of
the stomach was formerly exaggerated, since it was held to be the
centre of the digestive system; and the mass of the food-stuffs
transformed by it was known as chyme, meaning by this term
a pulp differing far more in constitution from the raw materials
ingested than it does in reality. As it became recognised that
the action of the gastric juice is almost entirely confined to
protein, and that even this property is not limited to the stomach
but is common to the intestine also, a more reasonable conception
prevailed of the functional value of this viscus. The fact that
food remains a long time in the stomach is not enough to give it
a predominating importance in digestion. The surface of the
stomach being relatively small in comparison with the ample
surface of the intestine, while it secretes an acid peculiar to itself,
it would be necessary (in order that the gastric juice may act
effectively) to compensate the limited surface of the organ by a
prolonged stay of the food within it. It has, on the contrary, been
proved, as we shall see, that food remains longer in the small
intestine as a whole than it does in the stomach. Lastly, it is
important to note that surgeons (Czerny, Kaiser and others) have
succeeded in keeping dogs and man in good condition for months
and even years after the excision of practically the whole of the
stomach. These facts show that the stomach is in no sense
absolutely essential to life. In another connection we shall
analyse the details and effects of the operation.
Two methods are employed to study the digestive action of the
gastric juice : that of natural digestion, which consists in observ-
ing the changes the food undergoes in the stomach (when intro-
duced in muslin bags by fistula) ; and that of artificial digestion in
vitro, in which the various foods are brought into contact with
natural or artificial gastric juice, at a proper temperature. The
first method, inaugurated by Beaumont, serves to give an idea of
the process as a whole ; the second, instituted by Eeaumur and
Spallanzani, yields a minute analysis of the different phases of the
process and the various products resulting from it.
It is easy with artificial digestions to show that the funda-
mental digestive action of the gastric juice consists in the so-
called peptonising of the proteins, by which these substances,
in DIGESTION IN THE MOUTH AND STOMACH 171
whether dissolved, or coagulated and insoluble, are transformed
into soluble and readily diffusible substances, called by Lehmann
peptones.
We cannot enter upon the exposition and critical analysis of
the various opinions successively put forward as to the nature of
peptonisation, and must confine ourselves to enumerating the
more positive of the experimental data : —
(a) No protein is (caeteris paribus) more readily digested by
the gastric juice than fresh fibrin extracted from the blood, and it
was therefore chosen by Briicke as the common measure of com-
parison between the digestive power of artificial and of natural
gastric juice. Next to fresh fibrin, casein is the most rapidly
digested ; next, boiled fibrin ; next again, coagulated egg-white.
As a rule it may be said that proteins of animal origin are digested
more easily than those of vegetable origin.
(6) Apart from the disparate nature of the proteins, the rapidity
of their digestion and solution depends on the degree of tem-
perature, the amount of pepsin, and the amount of acid which
the digestive juice contains. The optimum degree of temperature
is approximately that which is normal to the body. Below 35° C.
digestion is retarded, at 0° C. it is entirely suspended. The
amount of pepsin required to obtain a marked digestive action is
very small, certainly less than O067 per cent. According, how-
ever, to Schlitz (infra), when the amount of the enzyme is
increased, the quantity of acid and protein to be digested remain-
ing constant, then on estimating at regular intervals the amount
of protein dissolved, it is found that the rapidity of digestion
increases in proportion with the square root of the concentration of
the pepsin. If the amount of acid is varied, while the amount of
pepsin and of protein remains constant, it is found that excess
or deficit of acid retards or suspends digestion, while the
optimum amount of acid varies with the nature of the protein to
be digested (e.g. for fibrin the optimum is 0'9 per cent of hydro-
chloric acid, for coagulated egg-white on the contrary it is 1'2-1'G
per cent).
An admirable method for the quantitative determination of the proteo-
lytic power of the gastric juice and therefore of its pepsin content is based
upon the Schiitz law. This method, as first described by Mett (1894), can
also be used for testing the digestive power of trypsin, and is as follows : —
Fresh, liquid egg-white is aspirated into a glass tube with a lumen of
1-2 mm., which is plunged for one minute into water heated to 95° C. The
tube of coagulated albumin is then slowly cooked, and cut with a file into
small pieces, taking care that the cylinders of egg-white fit exactly the
end of each tube, so that no empty space is left in the latter. The glass tubes
are then plunged into 1-2 c.c. of the digestive fluid and left for 10 hours at a
temperature of 37-40° C. The albumin is evenly dissolved during this time
from the outer end of the tube inwards. At the end of the time the length
of the little tube and of the column of egg-white left undissolved are
measured. The difference gives the length of the cylinder of digested egg-
172 PHYSIOLOGY CHAP.
albumin. Since by Schiitz' law the rate of digestion or amount of protein
dissolved in the time unit are proportional to the square root of the quantity
of ferment, the quantity of pepsin or trypsin contained in the specimen
investigated must equal the square of the length of the column of egg-white
which it has digested in the given period. Supposing, e.g., that the gastric
juice A dissolves a column of albumin of 2 mm. while the juice B dissolves
one of 3 mm., it follows that the amount of pepsin present is as 4 : 9.
(c) The presence of the digestive products, particularly of
peptones, delays the final digestion of proteins and eventually
suspends it. If the mixture be then diluted with water, digestion
is resumed. If the peptones are removed by diffusion through a
dialyser as fast as they are formed, so that the original concentra-
tion of pepsin and acid is maintained, the mixture recovers its
initial digestive force. This must occur during natural digestion
in the stomach, because the peptones are absorbed as fast as they
are formed. In fact, only a mere trace of them can be found in
the contents of the stomach during the digestion of protein.
Briicke, on the strength of this, assumes that pepsin undergoes no
change during its digestive action. Griitzner's latest results,
however, make it probable that a little of the pepsin is consumed,
or loses its enzymatic properties (possibly by combining with other
colloidal substances), because even under the most favourable
circumstances the digestive power of any juice declines slowly.
(d) The addition of concentrated alkalies or acids destroys
the digestive action of pepsin, as does heating to 70° C. Bile, too,
suspends the action of gastric digestion in vitro, even in such a
small quantity that the acidity of the juice is not neutralised.
This seems, however, not to occur during natural gastric
digestion, since Oddi noted no digestive disorders in dogs in
which the gall-bladder had been put in communication with the
abdominal cavity by a fistula. It is probable that the bile poured
into the stomach under these conditions is rapidly absorbed
again without admixture with the gastric contents. Or it may
be assumed that the absence of digestive disturbance is due to
the fact that in dogs the suspension of the gastric function is not
of much importance, since it is readily compensated by a more
active duodenal digestion.
(e) The peptonisation of proteins by the gastric juice is not
immediate, but takes place in stages, several intermediate substances
being formed before reaching the end-substances represented by
the peptones — by a process analogous to the action of saliva on
starch. These modifications of protein by the gastric juice can
only be demonstrated by prolonged artificial digestion. After
some hours of digestion in vitro (at 35-45° C.) of a given quantity
of boiled fibrin (or cubes of coagulated egg-albumin) in a very
active, artificial gastric juice, at least three different kinds of
proteins can be detected in the mixture: an acid albumin or
in DIGESTION IN THE MOUTH AND STOMACH 173
syntonin, a proteose (formerly called by Schinidt-Miihlheim pro-
peptone), and a peptone.
Syntonin is the first stage in the transformation of fibrin effected by the
gastric juice. When the liquid is slowly neutralised by successive drops of
sodium carbonate solution, the syntonin precipitates, and can be separated
by filtration. To convert boiled fibrin into syntonin, it is only necessary to
use a simple sohitioii of 1 per cent HC1, keeping it in the warm chamber for
1-2 days. But if a little pepsin be added to the acid, the conversion into
syntonin is much accelerated. Fluid egg-white, on the contrary, according
to Meissner, is converted into syntonin in a few minutes, at 40° C. in simple
acid solution.
The proteose differs from peptone in being precipitated with acetic acid
and potassium ferrocyanide in the cold, and redissolved on heating. With
concentrated nitric acid there is also a precipitate which disappears 011
warming and comes back on cooling. When treated with ammonium
sulphate, it is thrown out like all other proteins, and this is the best
method for separating and estimating the peptone, which remains in solution
and passes through the filter.
The peptone which remains after separation of all the other proteins
from the digestive mixture, occurs in comparatively small quantities, showing
that gastric digestion is only partial, and is mainly a preparation of the
alimentary proteins for more complete digestion in the intestine. On add-
ing excess of caustic soda or potash and a few drops of copper sulphate to the
mixture, it becomes pink (biuret reaction). But proteoses also give the
same reaction. In a faintly acid solution the peptones precipitate with
phosphotungstic and phosphomolybdic acid, which are therefore used for
the isolation of peptone from all the other proteins. It is to be noted that
commercial peptone contains a large amount of proteose and very little true
peptone.
The proteolytic or peptonising process by which fibrin, egg-
albumin, and the other proteins are transformed into syntonin,
proteose, and peptone has been the subject of numerous and
minute researches, particularly by Klihne and his school ; these
are to be found in special treatises of chemical physiology. Here
we must confine ourselves to stating that the collective term
proteose includes several similar substances, which are dis-
tinguished from one another by various more or less definite
chemical characteristics, and that the end-products or peptones
must also be distinguished according to the nature of the original
protein from which they are derived.
This sequence of the transformations of proteins is not due
to any specific action of the gastric enzyme : it can be obtained
artificially by prolonged boiling with plain water or, better,
dilute mineral acids, or by steam at high pressure, by treat-
ment with strong alkalies, lastly by the putrefactive processes
produced by bacteria. According to Neumeister, however, the
products obtained by these different methods are not identical.
The gastric juice has a solvent action upon all proteins except
certain sclero-proteins. It transforms collagenic substances into
gelatin, which loses its faculty of coagulation, and is converted
into the so-called gelatin-peptone. Mucin, too, is converted into
174 PHYSIOLOGY CHAP.
a carbohydrate substance akin to the peptones. On the other
hand, the gastric juice has no effect on keratin, elastin, and certain
other substances of this group.
The analysis of the percentage composition of proteins, pro-
teoses, and peptones, as performed by Kiihne and Chittenden,
suggests that the proteolytic process effected by the pepsin and
gastric juice consists not so much in a profound alteration of the
structure of the large original protein molecule, as in its sub-
division, accompanied by hydration, i.e. taking up of water. This
theoretical concept explains why many properties are common to
all the chemical aggregates represented by the products of diges-
tion— in particular, the great facility with which the peptones
and their amino-acid derivatives are reconverted into natural
protein in order that the body may utilise them.
Gastric juice acts on the caseinogeu of milk and clots it
in virtue of its chymosin or rennin, which (as we saw in the
last chapter) is an enzyme distinct from pepsin. According to
Hammarsten's admirable researches, this curdling is a process
quite distinct from the flocky precipitation of caseinogen, which
takes place in the presence of hydrochloric acid, and redissolves
on neutralisation. Chymosin splits the caseinogen of milk into
two substances — a proteose, which remains dissolved in the serum
of milk, and is not precipitated by boiling or the addition of acids,
and the so-called casein or paracasein, which in combination with
the calcium salts of milk forms the true clot or cheese, which is
then digested by the action of the pepsin and hydrochloric acid.
A phenomenon apparently analogous with curdling is that
first described by Danilewsky (1886) of the precipitation of a
clot from a highly concentrated solution of proteoses and peptones
(Witte's peptone) by chymosin, pepsin, and papain, as well as by
extracts of many organs (pancreas, liver, small intestine, etc.). If
the mixture is placed in the thermostat at 35° C., a more or less
abundant precipitate is formed after a certain time, to which
Sawjawlow gave the name of plastein and Kurajew of coagulose,
and as to the nature of which nothing definite is known.
Since the normal stomach (or intestine) never contains a
concentrated solution of proteoses and peptones, Danilewsky's
phenomenon cannot be utilised in the complex study of digestion.
It was believed for a long time that the gastric juice had no
important action on fats, starches, and sugars. According, however,
to Cash (1880) and Ogata (1881), neutral fats can be split up in
a minor degree, with liberation of fatty acids. Volhard (1900-2)
demonstrated a lipolytic ferment in the gastric juice. His pupil,
Stade, not only confirmed the existence of this ferment, but also
showed that it conforms to the Schiitz law.
On the strength of this, Connstein (1904) concluded that the
lipolytic ferment is of great importance in the assimilation of
in DIGESTION IN THE MOUTH AND STOMACH 175
certain fats, particularly where, as in milk, the fats are emulsified.
This especially affects the new-born, who have no pancreas to
secrete ferments. The fact that after extirpation or destruction
of the pancreas there can still be a certain cleavage and assimila-
tion of alimentary fats, finds partial explanation by the presence
of a lipolytic ferment in the gastric juice.
According to Nasse, hydrochloric acid has some solvent
action on starch, transforming it into amidulin or soluble starch,
which is then, according to Briicke, converted into erythrodextrin ;
according to Leube, saccharose and lactose are split into mono-
saccharides.
VI. The influence of the spleen on the digestion effected by
the gastric juice deserves special consideration. This point was
taken up in our laboratory by Tarulli and Pascucci (1901), who
repeatedly compared on different dogs the digestive activity of
the gastric juice, before and some days or weeks after the extir-
pation of the spleen, as well as the digestive power of the gastric
juice in splenectoniised animals before and after administration of
a watery infusion of congested spleen, i.e. spleen excised from dogs
in full digestion.
Tarulli and Pascucci collected the gastric juice from a fistula
made in large dogs by Claude Bernard's method. Before feeding
them with the experimental meal (100 grms. cartilage and tendons)
which was to promote the flow of gastric secretion, they were
given a preparatory meal (500 grins, cooked meat, 500 grms.
broth, 200 grms. bread), with the object as far as possible of
exhausting the pepsin accumulated in the gastric glands; and
after 16 hours the mucous membrane of the stomach was washed
out with an isotonic and slightly warmed solution of sodium
chloride.
For digestion in vitro, a small cube of boiled egg -white
weighing 1 grm. was placed in contact with 10 c.c. pure gastric,
juice at a temperature of 39° C. for 24 hours. From the loss of
weight in the egg-albumin, the digestive power of the gastric
juice could be determined with sufficient accuracy.
The results of the experiments performed by this method may
be summarised in the two following propositions : —
(a) After extirpation of the spleen the digestive power of the
gastric juice is constantly weakened in a greater or less degree.
(6) The administration by the mouth of an infusion of con-
gested spleen 8 hours before the "experimental meal increased the
digestive power again for one, two, or even three days.
In order to form a concrete idea of these effects, three series of
experiments performed on three dogs may be studied in a diagram
(Fig. 58, A B C).
It should be noted that the lowering of the digestive power of
the gastric juice after splenectomy is apparent not merely in the
176
CHAP
first days after the operation, but even two to three months after
the removal of the spleen. On the other hand, if splenic extract
from an insufficiently congested spleen (excised 2-3 hours after
food, or from fasting animals) be administered to the splenectomised
animal by the gastric sound, there is no perceptible increase of
digestive power in the gastric juice : whereas this is constantly
Fio. 5S. — Diagram to show digestive power of gastric juice before and after splenectomy, and
before and after administration of extract of congested spleen. (Tarulli and Pascucci.) The
ordinates express the amount of boiled egg-white digested in cgrms. ; the abscissa lines indicate
the days on which the experiments were made ; J, indicates the fall of digestive power con-
sequent on ablation of spleen ; f shows the rise due to dosage with extract of congested
spleen.
the case when a well-congested spleen (excised 5-6 hours after a
meal) is used for the extract.
These results seem on the whole to agree with the old
hypothesis of Baccelli as regards the influence of the spleen upon
gastric digestion. It is, however, desirable to obtain more
definite knowledge of this influence. From what was said above
(p. 121), it seems that we may logically assume that the spleen
during gastric activity elaborates a pepsinogenic substance which,
when carried into the circulation and absorbed by the gastric glands,
increases the amount, of pepsin secreted.
in DIGESTION IN THE MOUTH AND STOMACH 177
VII. When we pass from digestion in vitro to consider the
natural digestion of food in the living stomach, a preliminary
question at once arises, to the effect that it is not possible from
the peptonising power of the stomach, as described above, to arrive
at any conclusion as to the process and the degree of digestion
normally carried on in the stomach. How far do proteins undergo
peptonisation in the stomach before they pass through the pylorus?
Is it only the solid or coagulated proteins that are wholly or
partially peptonised in the stomach, or the natural proteins as
well, which we ingest already dissolved ?
With the object of solving this problem, Jaworski and
Gluzinski (1885) performed a series of experiments in the medical
clinic of Cracow upon healthy individuals and on those who
suffered more or less from digestive trouble, pumping out the
contents of the stomach at different periods after a meal, in order
especially to determine the quantity of pepsin contained, and the
degree of acidity. The gastric contents of a healthy man pumped
out three-quarters of an hour or one hour after the ingestion of
egg-albumin gave no peptone or syntonin reaction. Seven hours
after a meal of beefsteak the gastric contents of a healthy man,
which were very abundant and acid, contained many fragments of
meat, but only traces of peptone, although the filtrate was capable
of digesting bits of coagulated egg-white in the warm chamber, and
then yielded a strong peptone reaction. On the other hand, in a
person suffering i'rom febrile intestinal catarrh, the stomach, half
an hour after the ingestion of an egg, yielded a highly acid fluid,
which contained fragments of coagulated egg-albumin, and gave a
strong peptone reaction.
From a number of fairly concordant experiments, these authors
concluded that the formation of digestive products in the stomach
is usually very small, and that under normal conditions of gastric
digestion an accumulation of such products was never present.
In pathological conditions, on the other hand, the acidity of the
gastric juice and the amount of digestive products might be very
much increased. They concluded that the egg -albumin intro-
duced passed after a certain time (1 or 1£ hours) into the iatestine,
almost entirely undigested, and that the more quickly the stomach
was evacuated, the more normal was its function. So that, accord-
ing to Jaworski and Gluzinski, the stomach must be regarded less
as an organ of chemical digestion, than as a receiver providing for
the gradual transit of the food into the intestine where true
digestion takes place. Gastric disturbance is thus the consequence
of abnormally increased digestive chemistry.
This theory, which tends to minimise the digestive importance
of the stomach, appears to us to be exaggerated. These observers
have not reckoned with the probability that the stomach walls are
capable of absorbing peptone as rapidly as it is formed, so that it
VOL. II N
178 PHYSIOLOGY CHAP.
never accumulates in the chyme or pulp of the gastric contents
during digestion. If this accumulation can take place under
pathological conditions, the phenomenon most likely depends on
the reduced absorbing capacity of the epithelium, consequent on
its catarrhal alterations.
Still it is undeniable that the peptonisation of proteins is very
imperfectly accomplished in the stomach, the dissolved protein
passing from the pylorus to the intestine before it has time to
become peptonised. This is evident from the observations made
by Busch (1858) on the famous case of fistula established in the
upper part of the jejunum in a woman of thirty-one. Four hours
after ingestion of raw egg-white, a ropy fluid which was faintly
alkaline, mixed with bile, and free of coagulum, began to flow
from the upper end of the intestine ; on dilution with water and
heating, or treatment with nitric acid, this coagulated in large
flocculi. It follows that a considerable part of the egg-albumin
ingested passes not only the stomach but also the duodenum,
without being attacked by the digestive juices. We shall return
elsewhere to the significance of this fact.
Our knowledge of the changes which natural food-stuffs and
viands, i.e. foods modified by cooking and other manipulations,
undergo in the living stomach, rests more particularly on the
classical work of Frerichs and Schroder, as confirmed by later
observers.
Milk is curdled previous to peptonisation. The caseinogen of
cows' and goats' milk forms a firm clot which is more resistant to
the action of gastric juice than the caseinogen of human milk,
the latter accordingly being the most suited for the alimentation
of infants.
Of muscular flesh, viscera, and membranes of animals the
collagenous substances of the connective tissues are first digested ;
they soften and become transparent and eventually dissolve ; next
follows the digestion of the muscular fibrils, and parenchymatous
cells. The fat which infiltrates the connective tissues, and that
with which many viands are impregnated, resists the digestive
action of the gastric juice, and greatly delays the digestion of the
proteins of which tissue protoplasm is built up. For this reason
pork is more difficult to digest than the lean meat of beef or veal.
Bone, too, is digested by the combined action of the hydro-
chloric acid which attacks the phosphates and carbonates of
calcium, converting them into soluble carbonates and phosphates,
and the pepsin which digests the ossein.
Vegetables and plant tissues in general are more slowly
digested than animal tissues, owing especially to the comparative
resistance to the action of gastric juice of the cellulose and starch
which surround the proteins. Bread, which is the commonest
form of food, is reduced to a soft and partially digested pulp in
in DIGESTION IN THE MOUTH AND STOMACH 179
the niouth, and undergoes few changes in the stomach from the
action of the gastric juice, which is confined to starting peptonisa-
tion in the gluten.
The duration of gastric digestion, i.e. the evacuation by the
stomach of the food, varies with the quantity and quality of the
latter, according to the individual and to the more or less normal
state of the digestive organs. Busch stated that after a copious
meal, the flow from the upper end of the fistula in the woman
above referred to commenced about half an hour after the meal,
and almost or entirely ceased after 3-4 hours.
Many of the sclero-proteins are refractory to the digestive action
of gastric juice : e.g. elastin, chitin, fibroin, chondrin. The nucleins,
too, are entirely exempt from the action of gastric juice, a fact
utilised by Miescher in separating them. Lastly, mucin and the
amyloid substances are also very resistant to the action of enzymes
in general.
The digestibility of the various foods or viands, i.e. the time
required for their digestion and absorption, can only be determined
in the stomach by the very relative criterion of their longer or
shorter retention there. The tables drawn up from the observa-
tions of Beaumont upon the famous Canadian, St. Martin, and his
gastric fistula, have therefore little value. The same may be said
of similar researches more recently made by other workers. Those
of Fermi, however, have a certain value, particularly from the
hygienic standpoint.
It is more important to form an approximate notion of the
time that the foods which consist mainly of the proteins that can
be digested by gastric juice remain in the stomach. In a dog
with a gastric fistula, 100 grms. of boiled egg-white enclosed in a
muslin bag are digested and disappear after 5 hours; 200 grms.
of boiled and minced meat were not completely digested in the
dog's stomach for over 12 hours (Schmidt - Miihlheim) ; 500
grms. raw minced meat were not all digested after 12 hours
(Barbera). All these facts confirm the statement that the task
of the stomach is confined to merely initiating the digestion of
proteins.
One very important function of the gastric juice is certainly
that of sterilising the food and drink ingested, by killing the
germs of putrefaction and innumerable pathogenic microbes, and
destroying and rendering innocuous the toxines and ptomaines
which are formed as the products of their metabolism, or from the
putrid corruption of the tissues. This sterilising and antiseptic
action, which constitutes one of the great defences of the organism
to many morbigenic causes, results from the incapacity of the
gastric juice to putrefy, and its antiseptic properties, discovered
by Spallanzani (1780). He proved in a series of ingenious ex-
periments, which Bunge justly praises as a model owing to the
180 PHYSIOLOGY CHAP.
scientific acumen they reveal, that the gastric juice kept for long
periods in closed vessels does not putrefy, although it gradually
loses its antiseptic properties ; that fresh meat steeped in gastric
juice keeps for a long time without putrefying ; that putrid
meat wholly or partially loses its bad smell in gastric juice, and
that the foetid odour disappears in proportion as it is digested,
when it is forcibly fed to ravens (attached to a thread by which it
can be examined at different intervals) ; lastly, that when en-
closed in finely perforated wooden tubes, and introduced into his
own stomach, " it lost even the slightest trace of putrescence."
Modern workers have shown that the process of putrefaction is
effected by specific bacteria, and that the antiseptic action of the
gastric juice is due to its free hydrochloric acid. In fact Sieber
(1879) found that the amount of HC1 necessary to retard the
putrefaction of meat is approximately equal to the normal acid
content of the gastric juice, and that a 0'5 per cent solution of
this acid suffices to hinder the development of the saprophytic
bacteria. Miquel (1884) confirmed this observation, and found
that the addition of 0'2-0'3 grins. HC1 to 100 c.c. beef-tea
prevented it from putrefying.
The antiseptic and bactericidal power of the gastric juice, of
course, has its limits. Some bacteria, particularly in the spore
stage, exhibit such resistance to chemical agents that they are
only destroyed by hydrochloric acid at a higher degree of concen-
tration than that of the gastric juice. Falk (1883) found the
latter inadequate to destroy the tubercle bacillus, while it did kill
the anthrax bacillus, leaving the spores intact (Perroncito). Ac-
cording to Nicati and Eietsch, and to Koch (1884), the cholera
bacillus is easily killed by a dilute solution of HC1, so that
introduction of this culture into the stomach of an animal does
not infect it. On the other hand, infection ensues if the culture is
introduced into the small intestine or the stomach, after injection
of a soda solution. According to Fermi (1894), the gastric juice
has no sterilising action on hyphomycetes and blastomycetes.
which therefore develop in it and alter its digestive activity. The
bacteria of lactic and butyric acid fermentation also seem to resist
the gastric juice, since after ingestion of much carbohydrate there
is nearly always a slight fermentation with development of lactic
and butyric acid. With abnormal catarrhal conditions of the
gastric mucosa, the amount of free HC1 in the gastric juice
diminishes in proportion with the increased secretion of the
alkaline mucus. Under these conditions all the bacteria that
excite fermentation, particularly those of lactic, butyric, and also
acetic and alcoholic fermentation, are able to germinate freely in
the stomach. In consequence of this fermentation lactic, butyric,
and acetic acid and alcohol develop at the expense of the carbo-
hydrates ingested. At the same time gases are developed, i.e.
in DIGESTION IN THE MOUTH AND STOMACH 181
carbonic acid, hydrogen, methane or marsh gas, and occasionally
sulphuric acid (Kuhn, Boas, 1892).
VIII. The effects of complete or almost complete resection of
the stomach are highly important from the physiological point
of view, in order to form a clear concept of the significance as
a whole of its digestive and protective functions.
The dog which survived the almost complete extirpation of its
stomach by Czerny and Kaiser, was able 2 months after the
operation to nourish itself on the mixed diet of a normal dog,
without vomiting or other disturbance. Its weight, 5850 grms.
previous to operation, rose in 9 months to 7000 grrns. The
faeces were normal in constitution. When it was killed 6 years
later the post-mortem showed that only a small portion of the
stomach was left near the cardia, which had assumed the form of
a bladder filled with food.
Ludwig and his pupil Ogata employed another method to
suppress the influence of the stomach on the digestion. They
introduced the food directly into the duodenum by a fistula made
near the pylorus, and to prevent the gastric juice from entering
the intestine, closed the pylorus by a small rubber balloon, the
distension of which was regulated by means of water introduced
through the neck of the balloon, which projected from the gastric
fistula. The various foods introduced in large quantities directly
into the duodenum (beaten-up eggs, minced meat) were perfectly
digested without producing any disturbance. Two injections a
day sufficed to keep up the animal's weight. Microscopic examin-
ation of the faeces showed that the connective tissue of raw meat
was not perfectly digested ; boiled flesh was not digested, and was
excreted by the rectum after a few hours, little or not at all
modified. Raw pork was hardly digested at all, cooked pork was
to a much larger ex-tent. These authors concluded that the
stomach was not absolutely necessary to the nutrition of the body,
either as a reservoir of food or in the formation of gastric juice.
In 1893 Carvallo and Pachon successfully repeated the
almost total extirpation of the stomach on a dog ; in the first
20 days after the operation, the animal only tolerated milk,
which was imperfectly digested. Two months later it was still
unable to digest the connective tissue of meat. Three months or
more from the operation, it was estimated from the nitrogen
content of the food and the faeces, that the digestion of cooked
foods had become almost normal, while that of raw foods was
still imperfect. Five months after, the animal was made to eat
putrid meat without any ill effects, a fact which does not minimise
the antiseptic importance of the gastric juice, because after such a
long period some functional adaptation might have occurred in
the animal to compensate for the lapsed antiseptic function of
the stomach.
182 PHYSIOLOGY CHAP.
De Filippi in another dog, on which Monari (1893) had
performed almost total gastrotomy, repeated the results of
Carvallo and Fachon. The latter (1894) also succeeded in keep-
ing a cat of 2 kilos, alive after total excision of the stomach.
After 25 days the animal weighed 420 grins, less. The milk
administered was not well digested, and clots of it were seen in
the faeces.
Among the cases of gastrotomy performed on man was one
recorded by Schuchardt, at Stettin. In 1895 he excised the
stomach of a patient to a somewhat smaller extent than in
Czerny's dog, and the man lived two and a half years in good
condition. At first he was only able to take small quantities
of food at each meal, but eventually he fed like a normal in-
dividual. At the post-mortem a small stomach (formed from a
portion of the cardia that had been left) was found which had
gradually acquired a capacity of 500 c.c.
The case of the Zurich surgeon Schlatter was more remarkable.
In 1897 he excised the whole stomach from a woman of fifty-six
in whom it had formed into a hard tumour. Being unable to
suture the cardia to the duodenum, he turned the latter into a
blind sac, and bound the cardia with a loop of the small intestine.
The patient survived this amazing operation, and increased in
weight. During the first 8 weeks the food had to be given
in very small quantities, and always in a liquid or finely
minced form.
A month after the operation, Wroblewski examined the
urine and faeces of this patient. For 13 days he found indole
in the urine to an amount in excess of the normal, and for 3 days
in normal quantity; the scatole was also rather in excess of
the normal.
Four months after the operation, Hoffmann made further
investigations on the same case and estimated the nitrogen intro-
duced with the food and eliminated with the faeces and urine.
He found that the proteins were digested and absorbed in a
ratio approximating to the normal. The same- was found of
the fats.
Five months after the operation, as an index of the putrid
processes in the intestine, he determined the amount and ratio of
the inorganic sulphuric acid and the ethereal sulphuric acid in
the urine. He concluded that, after 5 months, putrefaction was
not in excess of the normal. Seven months after the operation
the patient had put on about 6 kilos, weight.
In November 1898, Tricomi succeeded in operating on another
woman of forty -eight with complete success. This patient
suffered from diffuse cancer, like Schlatter's case, and here the
very small portion of the cardia that had remained healthy was
utilised for the suture, so that this may be regarded as an almost
total gastrotomy. On suturing the duodenum into a blind sac,
the continuity of the digestive canal was re-established by uniting
the cardia with the duodenum.
Some time after the operation, Deganello performed an in-
teresting series of experiments on this patient with the object of
determining (a) the digestion, assimilation, and consumption of
proteins, which he calculated from the amount of nitrogen intro-
duced and excreted by the faeces and urine ; (&) the intensity of
the putrefactive processes in the intestine, calculating from the
ratio between the inorganic and the conjugated sulphuric acid, and
the amount of aromatic substances in the urine, more particularly
of the phenol, indigo blue, and indigo red.
The most interesting of his results may be summarised as
follows : —
(a) Forty days after the operation (first period in Deganello's
experiments) the digestion and assimilation of nitrogenous sub-
stances were not normal. The faeces, under the microscope, showed
almost intact muscle fibres ; and of the ingested nitrogen 18'22 per
cent was eliminated with the faeces, the physiological average of
excreted nitrogen not exceeding 6-11 per cent.
(ft) At this time the faeces also gave indications of very
intense putrefaction, as shown not merely by their foetid odour,
but also by the marked reaction of indigo blue and red, and by
the ratio between the ethereal and the inorganic sulphuric acid of
the urine, which had altered from 1 :4'5 to 1 : 1>P72.
(y) Three months after the operation (second experimental
period) the digestion and assimilation of proteins had considerably
improved, the nitrogen excreted in the faeces having come down
to 12'92 per cent of the nitrogen ingested. This agrees perfectly
with the data of Carvallo and Pachon, De Filippi, and Hoffmann,
who made their observations some time after the operation and
found that nitrogen assimilation was almost normal.
(8) In this second period the ratio between the ethereal and
inorganic sulphuric acid varied between 1 : 8'4 and 1 : 5*6, showing
a marked diminution of the putrefactive processes in the intestine
as compared with the first period. This result agreed with that
obtained by Hoffmann, who investigated Schlatter's patient 5
months after the operation, and found the ratio almost normal.
From these complex results we may conclude that the
stomach is not absolutely indispensable to life. After its total
resection the digestion and assimilation of proteins diminish in a
first period, while the putrefactive processes of the intestine are
much increased. In a second period all these processes are
improved and gradually approximate to the normal, by a process
of compensation as to the nature of which we are ignorant. At
the end of February 1900 (i.e. more than 2 years after the
operation) this patient was reported by the surgeon to be well, and
184
PHYSIOLOGY
CHAP.
able to take nourishment of all kinds in frequent, though not
abundant meals.
IX. While the stomach is, in virtue of its glands, a digesting
organ, it is from its muscular coats an organ of special movements,
which serve in the first place to churn up the iugesta and bring
them into contact with the gastric juice, and in the second place,
to propel the semi-digested chyme onwards into the duodenum.
Beneath the external serous coat the stomach has three
layers of plain muscular tissue. These are (from the direction of
their fibres) the longitudinal (outer), the circular (middle), and
the oblique (inner). The longitudinal fibres are directly con-
tinuous with those of the oesophagus; they radiate from the
FIG. 59.— A, section through pyloric ]>art of stomach and commencement of duodenum, from
specimen hardened in situ. (J. Symington.) a, a, a, longitudinal folds of mucous membrane in
pyloric part of stomach ; b, section of mucous membrane ; c, circular muscular fibres of
stomach ; the longitudinal fibres are just visible to the naked eye as a narrow line internal to
the circular fibres ; D, duodenum ; P, pyloric orifice. B, diagrammatic view in perspective of
portion of coats of stomach and duodenum, including pylorus. (Allen Thomson.) g, inner
surface of gastric mucous membrane; g', section of mucous membrane with pyloric gastric
glands ; v, villous surface of mucous membrane of duodenum ; i, section of same with crypts
of Lieberkiihn ; p, p, ridge of pyloric ring, with section of its component parts ; mi, circular
layer of muscular fibres, seen in the section to form pyloric sphincter; me, longitudinal
layer of muscular fibres ; s, serous covering.
cardiac orifice, are more abundant along the curvatures, and thinly
scattered over the remaining surface of the stomach as far as the
pylorus, where they form a thick uniform layer, which passes over
the pylorus and becomes continuous with the longitudinal fibres
of the duodenum. The circular fibres form a close and complete
layer over the whole of the stomach. At the pyloric end they
become much thicker, and at the pylorus itself they form a
bundle within a circular fold of the mucous membrane, known as
the pyloric sphincter. Lastly, the oblique fibres are continuous
with the circular fibres of the gullet on the left of the cardiac
orifice, where they form a considerable stratum ; from this point
they descend obliquely, and spread out in different directions
upon the anterior and posterior surfaces of the stomach ; they
disappear at the pyloric antrum, mingling with the circular fibres
which predominate there (Fig. 59).
In proportion as the stomach fills with food, it dilates, and
in DIGESTION IN THE MOUTH AND STOMACH 185
changes its form and position ; the lower, great curvature moves
forward, and the upper, small curvature turns backward. This is
effected, when the walls become distended, by a passive rotation of
the stomach round its axis, which passes through the fixed points
represented by the cardia and the pylorus.
As the stomach fills with food, a series of active movements are
set up which proceed from the cardia along the body of the
stomach, and terminate at the pyloric orifice. They are peristaltic
in character, the mass of ingesta being churned up, and driven
towards the pyloric antrum and back along the lower curvature,
so that the upper portion of the gastric contents is continually
forced down below. These peristaltic movements are sometimes
accompanied by antiperistaltic contractions, which originate in the
pylorus, and proceed towards the cardia, but usually stop about
half-way down the stomach. The double movement helps to
mix up the mass of ingesta, and to saturate it with the gastric
juice. At the beginning of digestion the contractions are weak
and irregular ; afterwards they become more active, to decrease and
die away when the formation of chyme is completed.
The evacuation of the stomach during digestion is commonly
supposed to be effected by a rhythmical closing and opening of the
pyloric sphincter.
These data are mainly due to the observations of Wepfer,
Schwartz, Haller, Spallanzani, Magendie, Beaumont. Wepfer
(1679) was the first to describe active peristaltic and anti-
peristaltic movements of the stomach ; Magendie (1838) first
noted a constriction of the stomach due to the muscles of the
pyloric antrum ; Beaumont (1834) first observed most of the
phenomena enumerated in man. Ponsgen (1882) published a
monograph on the motor functions of the stomach, which reviews
the entire literature of the subject, and cites over 500 authors.
Morat (1882) used a gastric sound attached to a large rubber
balloon with thin walls, which could be inflated with air, the
other end of the sound being connected with a tambour. With
this he recorded three kinds of abdominal movements on man and
dogs — respiratory (predominating), cardiac, and gastric ; but this
method obviously tells nothing as to the form and localisation of
the peristaltic movements.
Pfungen (1887), by the manometric method, succeeded in
counting on an average three contractions of the antrum per
minute, each lasting 6-12 sees. He noted, in confirmation of an
observation by Hofmeister and Schiitz, that ?olid bodies introduced
into the antrum were driven back towards the fundus of the
stomach by an antiperistaltic movement.
Moritz (1895), with an elastic balloon of medium size attached
to the end of a flexible sound passed through the oesophagus,
registered the variations of gastric pressure, and recorded the
186
PHYSIOLOGY
CHAP.
movements exactly. According to his observations the fundus
and the pyloric antrum must be distinguished: the former has
mainly a digestive, the latter a motor function, as exhibited in
rhythmical contractions varying in number from 2-6 per minute.
Siuce the antrum fills in consequence of slight peristaltic waves
in the fundus, which are set up under very low pressure (2-6 cm.
water), the passage of the solid constituents of the gastric contents
into the duodenum is prevented. But the balloon which Moritz
introduced into the fundus is unable to transmit the peristaltic
movements as they succeed each other in the individual segments,
and minimises or cancels their effect on intra-gastric pressure. On
the other hand (given the relatively small size of the pyloric
antrum, and the almost synchronous systolic or diastolic move-
ments of its walls), it is obvious
that the elastic balloon can re-
cord considerable rhythmical
variations of pressure, up to a
maximum of 50 cm. of water.
Ducceschi (1897) took up
this interesting question again
in Fano's laboratory, and pub-
lished an accurate account of
the excellent results he obtained,
which covered many lacunae and
conduced to a clear and satis-
FlG^±~hSCilHfio'Vf>Knus inc¥d.iafcPart°J factory theory of the active
stomach, i:obtamed with a sound introduced * J
into dog by gastric fistula. (Ducceschi.) The movements Of the Stomach in
lower tracing represents the respiratory move- -, ,• , • j. ,.
ments recorded by a Marey's pneumograph. relation to gastric digestion.
His experiments were carried
out on four large hounds previously provided with a gastric fistula.
This operation abolished the negative pressure which distends the
stomach ; its walls therefore tend to adhere, and a small balloon,
4-5 cm. in diameter, inserted between the two surfaces of the
abdominal walls, transmits the movements of the part of the
stomach in which it is placed to a tambour with tolerable
accuracy.
The. animal is made to lie quietly on its side on a table (at
least 6 hours after a meal) and the cannula placed in the fistula
is opened; through this the sound fitted with the balloon is
introduced into the part of the stomach to be explored. Next the
balloon and sound are emptied of air by aspiration, and filled with
water, and then connected with a vertical glass cylinder, closed
above by a cork provided with two glass tubes, one long and
dipping into the water, the other short and communicating with
the column of air above the water. On joining the latter to a
Marey's tambour, the gastric curves are directly recorded, the
respiratory curves often being registered as well by a second
in DIGESTION IN THE MOUTH AND STOMACH 187
tambour connected with a pneumograph. The distension of the
exploring balloon is regulated by raising or lowering the cylinder
which is fixed in a holder.
FIG. 61. — Oscillations of tone in cardiac stomach, complicated by more rapid contractions and
passive respiratory movements, recorded from dog, as in Fig. 60. (Ducceschi.) Time tracing
marks intervals of 5 sec.
When the sound is passed into the cardiac, fundic, or middle
region of the stomach in a state of comparative rest, slow, irregular
contractions, slight in degree, are observed, which are probably
automatic oscillations of tonicity in the
gastric muscles (Fig. 60). In a period of
greater motor activity, other more rapid,
simple contractions appear along the line
of this slow primary wave, which are com-
parable with those that commonly appear
in plain muscle (Fig. 61). These oscilla-
tions of tonus and contractions vary con-
siderably in duration and intensity ; they
are never regular and rhythmic. The
primary waves on an average last 50-60
sees., the secondary 15-30 sees.
If the glass cylinder be somewhat
raised so as to increase the swelling of the
balloon, and with it the distension of the
gastric walls, another form of movement
appears with a highly characteristic curve.
This is very probably an expression of the FIG 62._Tracings of peristeltic
peristaltic movement propagated through
the stomach from cardia to pylorus. A
schema of this movement is shown in
Fig. 62. More frequently, however, the
tracing of this wave is less simple, and is interrupted by slight
notches due to the respiratory movements ; the succession of these
is very irregular, and abortive forms and a variety of combina-
tions with the oscillations of tonicity already referred to are not
movements obtained under
same conditions as Fig. 60,
with sound introduced into
cardia and fundus of stomach.
(Ducceschi.)
188 PHYSIOLOGY CHAP.
infrequent. These waves have a period of 35-55 sees. ; their
amplitude usually exceeds the excursion of the writing lever.
When the sound is introduced into the pyloric antrum, a very
distinct form of rhythmical movement appears, consisting of
systoles and diastoles in regular succession, which are determined
by the total contraction or relaxation of the muscles of the antrum
(Fig. 63). Each revolution takes 10-30 sees., i.e. a shorter period
than each peristaltic wave. No other form of contraction due to
the tonic state of the walls is ever seen in the antrum, probably
because the circular fibres predominate so largely.
The study of the conditions which produce these movements
of the stomach and their co-ordination with the several phases
of gastric digestion was very incomplete prior to Ducceschi's
observations.
FIG. 63. — Rhythmical systolic and diastolic movements obtained with introduction of sound into
pyloric antrum. (Ducceschi.) A, the lower tracing represents the respiratory rhythm.
B, time tracing marks 10 sec.
According to some authors, the gastric movements after a meal
begin after a brief period of tonic contraction, i.e. shortly after the
ingestion of foods (Eberle, Blondlot, Brinton, Beaumont, Busch,
Kussmaul). Accerding to others, on the contrary, the meal is
followed by a period of tonic contraction lasting about an hour,
after which the movements set in with increasing intensity,
reaching their maximum after 3-4 hours (Magendie, Adelon,
Schiff, Leven). All, however, agree that liquid foods pass rapidly
through the pylorus into the duodenum a few minutes after
ingestion. The best observations have been made on man, or on
dogs with a duodenal fistula (Busch, Kiihne, Hirsch, v. Mering,
Moritz), which show that the contents of the stomach, particularly
the liquid parts, are spurted into the duodenum a few moments
after the meal.
Leven (1902) specially investigated the time during which
fluids remain in the stomach. A measured quantity of water was
administered to dogs that had fasted for 24 hours; they were
in DIGESTION IN THE MOUTH AND STOMACH 189
then killed at different periods, and the quantity of water left in
the stomach was measured. In the first 12 minutes nothing was
absorbed or expelled by the pylorus ; after 15 minutes evacuation
commenced and was completed after 30 minutes.
In children the water in the stomach can easily be detected
radioscopically. The rapidity of expulsion varies very much ; in
some children it begins at once, in others after 13 minutes. In
some the horizontal level of the fluid sinks gradually, no waves of
muscular contraction being perceptible ; 100-125 c.c. of water
required 8-13 minutes for evacuation; 250 c.c. 19 minutes; warm
water disappears faster than cold ; the presence of solids in the
stomach delays evacuation to a remarkable extent. In another
group of children muscular contraction obviously co-operates.
The time required by the stomach for evacuation varies consider-
ably, according to the nature and quantity of the food. Nearly every
one, however, agrees that after 5-7 hours the stomach is usually
almost empty, unless there has been an excessively abundant meal,
jis we saw in discussing gastric digestion.
By some the distension of the stomach walls by the presence
of food is held to be a mechanical stimulus to the excitation of
gastric movements. Spallanzani first pointed this out in birds.
A guinea-fowl that had fasted for a day was made to swallow
hazel-nuts, and its stomach watched through an aperture made in
the abdomen. "As long as the stomach contained only a few
nuts, no movement was visible, but as it became filled I saw it
swell out, and suddenly get flat again," i.e. it exhibited systoles
and diastoles similar to those observed in the dog's pyloric
antrum.
Schiitz observed regular peristaltic movements in a dog's
stomach, isolated frojn the body, after insufflations of air through
a cannula tied in the oesophagus. This is a reflex phenomenon,
discharged by the mechanical stimulus, and effected by the ganglion
plexus situated in the stomach.
Many authors have verified Magendie's discovery that a solid
body introduced into the pyloric antrum is at once shot out, and
falls into the fundus. This proves the excitability of the stomach
to mechanical stimuli, under conditions not far removed from the
physiological.
Some interesting details can be deduced from the work of
Ducceschi. Twenty-four hours after a meal the stomach is
immobile, its movements commencing immediately after food.
Introduction of an exploring balloon into the empty stomach,
however, at once excites the movements. In proportion as the
distension of the balloon increases by the introduction of a
constantly increasing amount of water, the gastric movements
become more ample while their rhythm is approximately constant.
There is, however, a limit to the distension of the stomach,
190 PHYSIOLOGY CHAP.
after which its movements diminish, and are finally abolished
(Fig. 64).
Fio. 64. — Tracings of pyloric rhythm and its variations under the influence of progressive incre-
ments of pressure. (Ducceschi.) At 1, the exploring balloon exerted very weak pressure on
the walls of the antrum ; at 2, the pressure was increased by addition of 50 c.c. water ; at 3,
4, 5, 6, 7, respectively, 50 c.c. water were added, by which the balloon became more and more
distended.
On exciting the stomach by a sound with a rough surface,
peristaltic movements are set up in the cardiac portion and fundus ;
in the region of the pyloric antrum, on the contrary, the rhythm
in DIGESTION IN THE MOUTH AND STOMACH 191
becomes disorganised, antiperistaltic waves occur, or there is
tetanic contraction of the walls (Figs. 65 and 66).
Fio. 65.— (Left.) Tracing or pyloric rhythm and its modifications under rapid mechanical
excitation. (Ducceschi.) At A, the experimenter jerked the sound. Time tracing marks each
5 sec.
Fia. 66.— (Right.) Tracing from fundus of stomach. (Ducceschi.) At A, a marked increase of
movement was obtained by rapidly shifting the sound.
As regards the chemical stimuli that excite movements in the
stomach, Briicke ascribes great importance to the acid content of
the gastric juice, and proves that the movements are more or less
energetic in proportion with
the digestive work. Accord-
ing to Schiff, on the other
hand, chemical stimulation
of the stomach is more par-
ticularly due to copious
absorption of the digestive
product (peptone), which is
supported by the fact that
towards the end of digestion
there is constant reinforce-
ment of the movements of
the stomach.
DuCCeSChi, tO test these Fio- 67.— Tracing from cardiac stomach in which
, -11 . peristaltic movements were excited by introduc-
views experimentally, mtro- tion of HOI solution. (Ducceschi.) At o, 40 c.c.
Hnpprl 30 ^0 o p nf 0-1 ^ r>pr of °"25 Per cent HC1 were "'J^6'1 near the ex"
°-c- ° ploring balloon.
cent HC1 in the vicinity of
the exploring balloon, and found that in the region of the cardia
and fundus, particularly in the former, movements were clearly
excited, so much so as to produce typical peristaltic waves
(Fig. 67). In the region of the antruin, on the contrary, he
obtained quite different results; a O'l per cent solution of acid
192
PHYSIOLOGY
CHAP.
produced a delay in the systolic and diastolic rhythm ; stronger
solutions disorganised its course, and weakened its intensity ;
stronger solutions still were able to arrest it, or to incite anti-
peristaltic movements (Fig. 68).
Oil injecting solutions of peptone (1-2 per cent), Ducceschi
obtained increased tonicity of the gastric walls, and reinforcement
of the movements proper to the several regions of the stomach.
These and other effects of thermal and electrical stimuli on
the different parts of the stomach, led Ducceschi to conclude that
the excitability of the neuro-muscular apparatus of the stomach
did not merely vary quantitatively, but was also qualitatively
FIG. 68. — Tracing of rhythm in pyloric antrum, profoundly altered by excitation due to introduc-
tion of HC1 solution. (Uucceschi.) At B, 40 c.c. 0.4 per cent HC1 were injected near the
exploring balloon.
different and almost antagonistic in the region of the pyloric
antruni, as compared with other regions of the stomach.
This important conclusion agrees perfectly with the results
arrived at by Openchow^ki and his school (1889) in their valuable
work on the in nervation of the stomach, to which we shall refer
below.
Ducceschi reconstructs the motor functions of the stomach, in
co-ordination with its digestive processes, as follows : The descent
of the food into the stomach produces distension of its muscular
coats, which determines the peristaltic movements in the region
of the cardia, fundus, and body of the stomach, while the secretion
of the gastric juices occurs at the same time with an increasing
degree of acidity. This factor again reinforces the movements,
and in proportion as the digestive process advances, the tonic and
partially motor action of the peptone is added to the motor action
in DIGESTION IN THE MOUTH AND STOMACH 193
of the hydrochloric acid. This explains how the movements arise
and are kept up in the greater part of the stomach.
The rhythmical movements of the pyloric antrum follow a
different course, in consequence of the same mechanical and
chemical stimuli. The food which fills and distends this region
suppresses the rhythmical movements by the acidity of the juice
with which it is saturated and the solid particles which it contains,
obstructs the pyloric orifice, and produces antiperistaltic waves,
which carry the food back towards the middle and fundus of the
stomach. The pyloric antrum thus contributes to the churning up
and mixing of the ingesta, which is a necessary condition in order
that they may be saturated with the secretion, and digested.
At a certain stage in digestion the motor processes of the
stomach undergo an important modification. The solid con-
stituents of the food-stuffs are almost entirely dissolved, or at any
rate the mechanical effects of contact are much diminished, and
the acidity of the chyme reduced, on which the antiperistaltic
motions of the antrum subside, and it resumes the rhythmic
(systolic and diastolic) movements proper to it, while the tonic
spasm of the sphincters or pyloric valve ceases. Then at each
revolution of the antrum there is a little spurt of chyme into the
duodenum, synchronous with the opening diastole of the pyloric
orifice, as has often been observed directly in duodenal fistulae.
There is thus, according to Ducceschi, a complete correspondence
between the chemical and dynamical functions of the stomach,
which justifies the assumption that (like the adult heart, according
to Kronecker) it possesses a nervous, self -steering, regulating
apparatus, for its functions as a whole (infra).
Moritz (1901) has recently investigated the influence of the
nature of the food-stuffs on the rate of gastric evacuation in dogs
with duodenal fistulae and in man. The experiments on man
(principally on Moritz himself) were conducted as follows : Some
time after a test meal of known quantity and quality, a measured
amount of a known solution of some chemical product which can
be readily estimated and is not normally present in the ingesta,
was introduced into the stomach by the sound. After thoroughly
mixing the liquid with the gastric contents, by introducing air
into the stomach and violently shaking the body, a portion of the
mixture was drawn out again by the sound. From the lowered
concentration of the test substance (usually glucose), it was easy
to determine the quantity left behind in the stomach. Moritz
found that the mechanical consistency of the food was an essential
factor in the evacuation of the stomach. The gastric contents are
not passed on into the intestine in the form of solid pieces, nor
exclusively in the fluid state, but largely in the form of pulp.
Fluid foods (broth) are, however, more rapidly evacuated than
thick soups or sops.
VOL. II 0
194 PHYSIOLOGY CHAP.
The consistency of the food is not, of course, the sole factor that
determines the rate of gastric evacuation. If this were so, all
mobile fluids would leave the stomach with the same rapidity,
which is not the case. On introducing half a litre of water,
60 per cent is eliminated in 15 minutes, while if the same
quantity of beer is introduced, only 11 per cent is excreted.
Milk, soup, sops, again, stay longer in the stomach than would
be expected, judging merely from their consistency. Moritz
interprets this fact as meaning that all these substances (unlike
water, which is an indifferent substance) function as stronger
chemical, and partly also as mechanical stimuli, as shown also by
a greater secretion of acid. On the strength of this fact, Moritz
holds soups to be a food, particularly adapted to prepare the
stomach for the introduction of more solid viands.
The application of radioscopy (by admixture of bismuth sub-
nitrate with the food) to the study of the movements of the stomach
in digestion, has led to a distinct advance in methods and compara-
tive results. The most interesting researches in this direction are
those of Cannon (1898), and Eoux and Balthazard (1907), both
with the usual animals experimented on and with man.
According to these authors the stomach may functionally be
divided into two portions, the fundus (or cardia) and the pylorus.
The latter is mechanically the most active part of this organ, and
exhibits, radioscopically, ample peristaltic movements throughout
the whole period of digestion.
The cardiac region only shows rare waves of contraction which
propel the food-stuffs towards the fundus. In the fundic part the
chyme travels very slowly in the direction of the pyloric antrum.
The movements of the pyloric antrum are set up in the part
nearest the fundus (pre-antral constrictions), and are mainly
effected by the circular fibres ; the antrum contracts vigorously
and assumes the form of a tube. The (peristaltic) contraction
waves are separated, both in animals and in man, by an interval
of 10-20 sees. The pyloric orifice rarely opens in the first period of
digestion, while towards the close it relaxes in response to each
contraction of the antrum.
The chyme is almost stationary in the fundus : it passes slowly
into the pyloric antrum where the food is thoroughly mixed with
the digestive juices and dissolves, owing to the vigorous move-
ments in this region. The alimentary mass, while continually
passing from fundus to antrum, perpetually flows back (especially
in the first periods of digestion) from antrum to fundus owing to
the increased pressure, which gives rise to the peristaltic waves in
the antrum when the pylorus remains closed. The chyme passes
more quickly and in larger quantities into the intestine, in
proportion as it is softer and more liquid in consistency. The
pyloric orifice opposes the passage of solid foods. On mixing
in DIGESTION IN THE MOUTH AND STOMACH 195
some hard boluses of bismuth subnitrate with the soft foods, the
pyloric sphincter is seen, radioscopically, to close sharply on the
arrival of the bolus.
These results are particularly important because they confirm
to a great extent for uninjured man or animals, the observations
made by means of fistulae, or other methods, in which the normal
conditions of gastric digestion have been more or less modified.
X. Since it is one of the most important modifications of the
ordinary motor processes in the stomach, special attention must be
given to vomiting. In the majority of cases it is a pathological
phenomenon, but is under certain conditions a true physiological
act, by which the body relieves the stomach of excessive work, and
eliminates noxious substances ingested or developed in situ by
abnormal processes of fermentation. Vomiting is excited either
by excessive distension of the stomach, or by the acrid substances
developed in abnormal digestive processes, or by the action of the
so-called emetics which are particularly adapted to excite the
nervous mechanisms that give rise to vomiting.
The fundamental question in regard to the mechanism of
vomiting is to decide what part the stomach plays by its con-
tractions, and what is due to abdominal compression, which
consists in the synchronous contraction of the abdominal and
diaphragmatic muscles.
The older physicians held vomiting to be purely an effect of
the antiperistaltic movements of the stomach, with simultaneous
closure of the pylorus and dilatation of the cardia. Bayle and
Chirac, and after them Magendie, sustained the opposite opinion,
viz. that the stomach was passive in vomiting, and that the
process rests upon the violent impulse of abdominal com-
pression.
Schwartz demonstrated that the stomach, when exposed and
freed from the pressure of the abdominal muscles and diaphragm,
was no longer capable of emptying itself by vomiting on injection
of tartar emetic. He did not, however, deny the active participa-
tion of the stomach. Magendie (1813), went farther. He was
unable to convince himself of such participation, either by
palpation or by inspection. It appeared to him to be an
experimentum crucis that vomiting was accomplished perfectly
when the stomach was replaced by a pig's bladder filled with
water. Griannuzzi (1866) supported this theory by his observation
that curarised dogs could not vomit when tartar emetic was
injected.
But this fact does not prove that the stomach is passive, only
that vomiting requires the aid of abdominal compression. Tantini
(1825) was the first to prove this by a modification of Magendie's
experiment in which he substituted a bladder for the stomach,
but without interfering with the cardiac orifice. Under these
196 PHYSIOLOGY CHAP.
conditions the stomach was not evacuated in spite of the most
vigorous impulses of abdominal compression.
On the other hand, we know that in coughing and in defaeca-
tion, when the abdominal muscles and diaphragm come energetically
into play, there is no vomiting, because the stomach remains
passive. Schiff (1867) further noted that in certain nervous
affections vomiting is inhibited, notwithstanding the most
powerful efforts of abdominal compression. He also adduced the
fact that in fistula -dogs it has been proved by introducing a
finger in the direction of the cardia that it dilates actively during
vomiting, owing to the contraction of the longitudinal fibres
which spread out from the oesophagus into the cardia. In fact,
when these fibres were divided in the dog he found that vomiting
no longer occurred.
At the commencement of vomiting, Schwartz often observed
contraction of the longitudinal layer of gastric muscle fibres,
which commenced at the pylorus, and brought it nearer to the
fundus. The surgeon Patry (1863) made observations on vomiting
in a young man who was wounded after a heavy meal and had an
abdominal aperture and protrusion of the stomach. On replacing
it in the peritoneum vomiting ensued, during which strong but
slow contractions were seen from pylorus to cardia, until the
stomach had entirely emptied itself without assistance from the
diaphragm and abdominal muscles.
In order to demonstrate the active participation of the
stomach in vomiting, Openchowski (1889) paralysed its move-
ments by ligation of the thoracic aorta above the diaphragm.
After inoculations of apomorphine or lobeline he saw energetic
spasms of sickness, without the least regurgitation of the gastric
contents. On removing the ligature from the aorta, regurgitation
occurred regularly. He described the modifications of the normal
peristalsis of the stomach under the action of emetics (copper
sulphate, apomorphine). There is at first disquiet of the intestines,
then spasm of the pylorus, followed by contractions of the antrum,
which are propagated as antiperistaltic waves to the lower and
middle third of the stomach, while the upper or cardiac part
widens at the same time, so that the viscus finally assumes the
form of a pear with its dilated part turned upwards — the contents
of the stomach being forced out at the oesophagus. In most cases
the dilatation of the cardiac part precedes the antiperistaltic
motions of the remainder which (particularly at the pyloric
antrum) are the main factors in the act of vomiting. This cycle
of phenomena is repeated many times, periodically, in the form
of spasms.
Liittig (1873) was the first to note at the beginning of vomiting
a strong inspiration and closure of the glottis, which must produce
considerable negative pressure inside the thorax, sufficient to
in DIGESTION IN THE MOUTH AND STOMACH 197
aspirate the contents of the stomach into the oesophagus, if the
cardia be opened simultaneously. This mechanism is facilitated
by the simultaneous rise in abdominal pressure owing to the
contraction of the diaphragm and abdominal muscles. The
retching which precedes evacuation of the gastric contents is due
to this oesophageal aspiration.
Lastly, in vomiting, there is an elongation of the oesophagus,
caused by the contraction of its longitudinal fibres, and by the
movements of mouth, pharynx, and larynx, as thoroughly worked
out by Dzondi (1831). The closure of the pharyngo-nasal cavity
and glottis is effected by a mechanism identical with that which
occurs in the act of deglutition ; but, contrary to deglutition, the
tongue and roof of the mouth are not raised but are lowered,
because in vomiting the mouth must be open. According to
Dzondi the mouth, which is relaxed in deglutition, must contract
in vomiting, to resist the passage of the contents of the stomach
by the choanus.
XI. The innervation of the gastric muscles is still a very
obscure and imperfectly studied field. The observation of various
experimenters, particularly Hofmeister and Schiitz, to the effect
that the stomach, when excised from the body and brought into a
warm glass chamber, is capable, like the heart, of performing
spontaneous movements, shows that it possesses in itself all the
conditions necessary to its movements, — its automatic and reflex
centres being probably represented by the gangliated groups in
Auerbach's plexus. This fact, however, does not exclude the
controlling and regulating influence of the cerebrospinal nervous
system, transmitted to the stomach by way of the vagi and
splanchnics.
Longet first suggested that the vagi exercise a motor influence
on the stomach, which, however, in his opinion is manifested
only after a meal, and not on the empty stomach. S. Mayer,
Russo-Giliberti, and Morat confirmed this influence of excitation.
Division of the vagi, on the contrary, gives very uncertain
results: according to some the gastric movements persist (Magendie,
Bidder and Schmidt, Donders, Schiff) ; according to others they
are suspended or at least much attenuated (Eawitsch, Milne-
Edwards, Joh. Miiller, Longet).
A fact worth noting, as deduced from physiological research
and anatomical control, is that the two vagi are not (as commonly
stated in the text-books) distributed, the right to the posterior
surface and the left to the anterior surface of the stomach. Both
in the higher mammals and in man, the two vagi course together
and form in the lower part of the oesophagus, with fibres common
to both, one trunk which runs to the anterior plexus, and a second
which is continuous with the posterior gastric plexus (Ducceschi,
Dorello).
198 PHYSIOLOGY CHAP.
The action of the sympathetic system is less well established.
Some deny that it has any effect on the movements of the stomach
( Joh. Miiller, Oehl, Longet) ; others credit it with a motor influence
(Budge, Bonders, Brinton, Schiff, Adrian, Goltz, Kusso-Giliberti) ;
others, again, recognise in the splanchnics and the sympathetic
fibres from the caeliac plexus in general, inhibitory or moderator
nerves of the gastric motions (van Braam-Houckgeest, Morat,
Convers).
The numerous researches of Openchowski and his pupils, v.
Rosen, v. Knaut, Dobbert, Hlasko, Fransen, on rabbits, cats, and
dogs, which are collected in two publications (1889), led to a
remarkable consensus of results in regard to the central and
peripheral nervous mechanisms that regulate and co-ordinate the
movements of the stomach. In order to facilitate this point, Fig.
69 reproduces Openchowski's schema.
In the stomach of new-born rabbits, treated with gold chloride,
Openchowski discovered ganglionic nodules which are distinct in
structure and position from those of Auerbach's plexus, and
resemble Reinak's and Bidder's ganglia in the heart. They are
scattered in the serous coat, and are in relation with the fibres of
the vagus and the sympathetic system, which run to the stomach.
Eleven such groups can be distinguished in the cardia, and seven
in the pylorus (G G of figure). In the walls of the stomach they
are fewer, and consist of a smaller number of cells. He believes
that the movements of the stomach which persist after its separa-
tion from the cerebrospinal centres depend on these ganglia, to
which he assigns an automatic function. This part of Open-
chowski's theory calls for direct experimental confirmation.
According to the Dorpat physiologist, the cerebrospinal centres
on which the regulation of the movements of the stomach
depends, are situated in the posterior corpora quadrigemina, in the
nucleus of the corpora striata, the cortex of the sulcus cruciatus,
the olivary bodies, and the grey matter of the upper tract of the
spinal cord. The efferent paths run in the vagi, the splanchnics,
the spinal chain of the sympathetic, and the caeliac plexus. The
afferent paths leading directly or indirectly to these centres have
not been exactly determined, but must, as we shall see, be very
numerous.
Excitation of the median part of the sulcus cruciatus of
the cerebral cortex causes a slight dilatation of the cardia
associated with the contraction of the pylorus. It therefore
contains two centres which have an antagonistic action, probably
because they produce the contraction of the longitudinal muscle
fibres, which predominate at the cardiac orifice, and of the circular
fibres, which constitute the pyloric sphincter. The efferent paths
for these two centres run exclusively with the vagus nerves.
The caudate and lenticular nuclei contain more important
in DIGESTION IN THE MOUTH AND STOMACH 199
centres which act in the same way and with more effect, on both
cardia and pylorus, causing the former to dilate, and moderating
the movements of the latter, without, however, causing it to open.
The efferent paths from these centres also run in the vagi.
FIG. 69.— Diagram of nerves and nerve centres that regulate movements of stomach. (Openchowski.)
C, brain ; V, stomach ; MO, medulla oblongata ; MS, spinal cord ; 5-10, level of corresponding
dorsal vertebrae ; VSR, trunk of right vagus ; VS, trunk of left vagus ; ND, dilator nerve of
cardia ; NC, constrictor nerves ; c, plexus of Auerbach ; (7, ganglia^lescribed by Openchowski ;
S, S, fibres from sympathetic plexus, which are in relation with Auerbach's plexus. 1, Sulcus
cruciatus ; 2, corpus striatum ; 3, corpora quadrigemina ; K, nucleus of vagus ; o, olive ; 4, 4,
spinal centres for orifice of cardia. The black lines represent the nerves to the cardia ; the
broken lines the nerves to the pylorus ; the broken and dotted lines the nerves to the fundus
and body of stomach.
The principal cerebral centres for the movements of the
stomach lie in the posterior corpora quadrigemina, which influence
not merely the cardia and the pylorus, but also the entire body of
the stomach. Excitation of these produces a general constrictor
effect. The efferent fibres run for the most part in the vagi.
200 PHYSIOLOGY CHAP.
Other fibres traverse the anterior column of the spinal cord, and
leave by the anterior roots of the tract that extends from the 5th-
10th dorsal vertebrae ; they then unite with the splanchnics and
to a less extent with the sympathetic chain.
In the olives of the bulb there is, according to Openchowski,
an inhibitory centre that determines the opening of the pylorus
by fibres which descend in the cord, and unite after leaving it
with the sympathetic.
In the upper part of the cord, again, there are centres, which
on excitation cause the cardia to open. The efferent fibres descend
in the anterior cord, and then leave the anterior roots, and unite
with the dorsal sympathetic chain, with the aortic plexus, and the
small splanchnic.
Although the afferent paths, which by acting on these centres
may reflexly determine the movements of the stomach, have not
been fully worked out, it is proved by Openchowski's work that
excitation of the kidneys, uterus, bladder, loops of the intestine,
and sciatic of animals in which all the nerve paths and centres are
intact may induce opening of the cardia. This fact accounts
for reflex vomiting, which not seldom accompanies diseases of these
parts, like that which is easily induced in man merely by slight
mechanical stimulation of the roots of the tongue, the pharynx,
and the palate.
An important contribution to our knowledge of the significance
which must be attributed to the afferent paths, and, generally
speaking, to the peripheral stimuli, in the production and normal
course of vomiting has recently been made by A. Valenti (1906).
Experimenting with dogs and cats, he found that if a well-defined
zone of the pharyngeal mucous membrane was anaesthetised with
cocaine, between the lower part of the buccal cavity and the
higher part of the oesophagus, the animal lost the capacity of
expelling substances from the stomach, although on the action of
emetics (apomorphine, tartar emetic, copper sulphate) all the other
phenomena of vomiting were exhibited. This incapacity is due to
the fact that under such experimental conditions the active opening
of the cardiac sphincter does not come off. This opening is, how-
ever, a reflex act, due to excitation of the said zone of the pharyngeal
wall. According to Valenti this reflex has no connection with the
reflex of deglutition, the peripheral area of which lies, as we have
seen, in a more anterior region of the soft palate. In normal
vomiting this region of the mucous membrane is stimulated,
according to Valenti, by waves of peristaltic contraction from the
oesophageal walls, or more probably, perhaps, by the passage of
the saliva, which is regularly swallowed prior to vomiting.
Valenti's work accounts clearly for the mechanism of reflex
vomiting on tickling of the fauces, since it is evident, as we have
seen, that pharyngeal-oesophageal anaesthesia is capable of pre-
in DIGESTION IN THE MOUTH AND STOMACH 201
venting the cardia from dilating, while excitation of the same
region must, on the contrary, provoke a violent and forcible
dilatation of the cardia, and reflex emission of the gastric
contents.
Lastly, Muratori's experiments in our laboratory (1909) on dogs
with a gastric fistula, through which a long semi-rigid sound (pro-
vided with electrodes) can easily be passed to the various regions of
the mucous coat of the stomach, show that the whole surface is not
capable of exciting reflex vomiting on artificial stimulation with
electrical and mechanical stimuli. It is the cardiac region proper,
which is distinguished from the rest of the gastric mucous membrane
by the property of determining reflex vomiting, the pyloric region
being destitute of this capacity. Division of the vagi in the neck
abolishes all reflex vomiting, while sensibility to pain remains.
These observations of Muratori are not entirely new, Bulatowicz
(1858) having noted analogous data.
The theory of the mode in which the action of the many
centres of gastric motion is associated and co-ordinated in the
performance of the acts that normally occur in vomiting, has still
to be worked out. Certain observations of Openchowski, Tumas,
and Ducceschi, however, bear on this question.
Among the fibres of the vagus coming from the corpora striata,
Openchowski (1883) discovered in the rabbit a nerve which, on
peripheral excitation, produces contraction of the pylorus as well
as dilatation of the cardia. The two antagonistic effects, which
are eminently adapted to bring about or favour vomiting, are
synchronous.
Openchowski distinguishes two groups of emetics : those which
act directly on the centres, and those which promote vomiting by
reflex paths. Apomorphine and lobeline, which belong to the
first group, transmit the central excitation through the paths of
the spinal cord, so that it is a mistake to consider (as stated in
many text-books) that the vagus is the only nerve of vomiting.
With emetics of the first group vomiting becomes impossible after
the destruction of the corpora quadrigemina ; after division of the
cord or its anterior columns to the level of the 5th vertebra ; after
section of the thoracic chain of the sympathetic at the height of
the 6th and 7th ribs ; after extirpation of the 5th, 6th, and 7th
spinal roots ; lastly, after complete separation of the splanchnics.
Under all these conditions the characteristic movements of the
stomach also come to a standstill. It has hitherto proved impossible
to give any adequate explanation of these phenomena. Apomorphine
may perhaps paralyse the motor nerve fibres which end in the
cardia and upper third of the stomach, with simultaneous excita-
tion of the inhibitory fibres, which causes dilatation of the whole
cardiac region.
Valenti saw that interruption of the peripheral sensory paths
202 PHYSIOLOGY CHAP.
(anaesthesia of the vagi in the neck, anaesthesia of the glosso-
pharyngeal, anaesthesia of the pharyngo-oesophageal region) is
capable by itself of inhibiting evacuation of the stomach, even
when emetics with a central action (apomorphine) are administered.
This fact can be explained on the assumption that emetics with a
central action raise the excitability of the centre, on which the
normal stimuli reaching it by sensory paths can induce vomiting.
After complete anaesthesia of these sensory paths the hyper-
excitability of the centre produced by the emetic is not of itself
sufficient to determine vomiting.
The action of emetics of the second category (copper sulphate,
tartar emetic) is transmitted solely by the vagi, hence the
possibility of vomiting ceases when they are divided. In some
cases vomiting ceases in dogs after destruction of the corpora
quadrigemina and the corpora striata. According to certain
observations incidentally made by ourselves when studying the
cerebellum, partial destruction of the posterior corpora quadri-
gemina gives rise in dogs, for 4-5 days in succession, to repeated
vomiting, which then ceases entirely with the disappearance of
the excitatory phenomena. It is clear that the emetic action of
these substances is mainly due to reflexes by the afferent paths,
whatever the situation of the part on which they act. Vomiting,
in fact, follows not merely when the emetic is introduced into the
stomach, but also when it is injected into a loop of the intestine,
which explains the vomiting that accompanies certain intestinal
diseases.
It is still doubtful whether, in order to explain the specific
behaviour of the nerve centres in vomiting, we should assume the
existence of an isolated centre for vomiting, or a specific association
and co-ordination of the separate motor and inhibitory centres for
the different parts of the stomach as pointed out by Openchowski,
as well as active intervention of the bulbar respiratory centres.
Tumas (1887) assumed a unitary centre for vomiting, situated
bilaterally in the depth of the medulla oblongata near the calamus
scriptorius. He saw in effect that in dogs destruction of the
median line of this region made vomiting impossible. Openchowski,
on the contrary, doubted the existence of a special centre of
vomiting, and thought it probable that Tumas' results depend on
the interruption of the nerve paths which descend from the
corpora quadrigemina to the bulb, and thence to the anterior
columns of the spinal cord.
He showed by many observations made in collaboration with
Hlasko, that apomorphine-vomiting is inhibited after destruction
of the posterior corpora quadrigemina, while that from copper
sulphate is violently excited. This fact shows that there must be
two distinct central nuclei that act as centres for vomiting. He
further saw that vomiting ceases immediately after the section of
in DIGESTION IN THE MOUTH AND STOMACH 203
the cord above the striae acusticae, but after 4-5 hours apo-
morphine produces vomiting of a special kind, which sets in
suddenly, as if an inhibitory influence had expired, so that the
FIG. TO. — Tracing of rhythmical and periodic movements obtained in the pyloric region, after
extirpation of caeliac plexus. (Ducceschi.)
action of the spinal centres which are simultaneously trying to
induce vomiting, come into play. In any case, it is certain that
the respiratory centres of the bulb are quite distinct from the
vomiting centres. In fact, when the conditions for vomiting fail
FIG. 71. — Tracing of periodic movements in cardiac region, after extirpation of
caeliac plexus. (Ducceschi.)
owing to central lesions, an excessive tachypnea can be observed.
As on the other hand abdominal compression, i.e. the synchronous
contraction of diaphragm and abdominal muscles, intervenes
actively in the production of vomiting, we must, in order to
sustain the doctrine of a special unitary centre for vomiting also
204 PHYSIOLOGY CHAP.
show the existence of a centre for abdominal compression, closely
connected with the former, in which no one has yet succeeded.
Another fact worth noting, which may serve as a point of
departure for further work, is that observed by Ducceschi after
section of the vagi and caeliac plexus, as performed on dogs under
Fano's directions. While on section of the vagi there is, according
to Ducceschi, no very striking modification in the form and course
of the normal movements of the stomach, excision of the caeliac
plexus, which sends branches into the stomach in connection with
Auerbach's plexus, sets up movements with a periodic course,
which arise from the grouping and combination of rhythmical
movements, peristaltic waves, and oscillations of tonus, constituted
into successive groups of fairly regular form (Figs. 70 and 71).
This phenomenon (which recalls the analogous effect already
studied on the heart and in the respiratory movements) is never
seen under normal conditions. Subsequent division of the vagi
modifies the groups, without, however, suppressing them.
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Early Literature in general : —
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SPALLANZANI. Dissertazioni di fisica animale e vegetabile. Modena, 1780.
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Leipzig, 1826.
LEURET and LASSAIGNE. Rejherches physiologiques et chimiques pour servir a
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der Wissensch. zu Berlin, 1881-83.
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OPENCHOWSKI. Ibidem, 1883.
H. KRONECKER. Deutsche med. Wochenschrift, 1884.
S. MELTZER. Berliner klin. Wochenschrift, 1884.
MARCKWALD. Zeitschrift fur Biologic, 1887.
WASSILIEFF. Mittheilungen der Naturforsch. Gesellsch. in Bern, 1888.
KRONECKER and LUESCHER. Atti della R. Accademia dei Lincei, 1896.
LUESCHER. Habilitationsschrift. Miinchen, 1897.
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CANNON and MOSER. American Journal of Physiology, 1898.
EYKMANN. Pfliiger's Arch, xcix., 1903 (with critical review of previous work).
Chemistry of Gastric Digestion, in addition to the Text-books of LUDWIG,
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Physiology : —
BUSCH. Virchow's Archiv, 1858.
BRUCKE. Sitzungsber. d. Akad. d. Wissensch., 1859-69.
HAMMARSTEN. Abhandl. der k. Ges. der Wiss. Upsala, 1877.
SALKOWSKI. Virchow's Archiv, 1880.
JAWORSKI and GLUZINSKI. Zeitschr. f. klin. Med., 1885.
KUHNE and CHITTENDEN. Zeitschrift fur Biologic, 1883-84-86.
NEUMEISTEK. Ibidem, 1887-88.
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fiir Biologie, 1893.
CONNSTKIN. Ergebnisse der Physiologic, 1904 (contains bibliography of 150
publications on this subject).
Effects of Gastrotomy : —
KAISEK. Czerny's Beitiiige zur oper. Chir. Stuttgart, 1878.
OGATA. Du-Bois Reymond's Archiv, 1883.
MONARI and DE FILIPPI. Arch. ital. de biologic, 1894.
CARVALLO and PACHON. Achives de physiologic, 1896.
SCHLATTER. Correspondcnzblatt fur schweizer Arzte, 1897.
WROBLEWSKI. Centralbl. fiir Physiologic, 3897.
A. HOFFMANN. Munch, med. Wochenschrift, 1898.
TRICOMI. La Riforma medica, 1899.
BEGAN ELLO. Atti del R. Istituto veneto, 1899.
Movements and Innervation of Stomach and Vomiting : — •
SCHWARTZ. Dissertatio etc. de vomitu et motu intestinorum. Gottinga, 1750.
TANTINI. Annali univ. di medicina di Omodei, 1824.
PATRY. Bulletin de 1'Academie de med. xxviii., 1863.
GIANNUZZI. Centralbl. f'iir med. Wiss., 1865.
M. SCHIFF. Moleschott's Unters., 1867.
LUTTICH. Diss. Kiel, 1873.
PONSGEN. Die motorischen Vorrichtungen des meuschlichen Magens, etc. Strass-
burg, 1882.
HOFMEISTER and SCHUTZ. Archiv fiir exp. Pathol., 1886.
OPENCHOWSKI. Centralbl. fiir Phys., 1889.
MORAT. Lyonmed., 1882. Arch, de physiologic, 1894.
MORITZ. Zeitschrift fiir Biologie, 1895.
DUCCESCHI. Archivio per le scienze mediche, 1897. Settimana medica dello
sperimentale, 1897.
MAGNUS. Ergebnisse der Physiologic, 1903, 1908.
VALENTI. Centralblatt f. Physiologic, 1908.
CANNON. Amer. Journal of Phys. , 1898.
Roux and BALTHAZARD. Compte rendu de la Soc. Biol., 1908.
Recent English Literature : —
P. G. STILES. On the Rhythmic Activity of the Oesophagus and the Influence
upon it of Various Media. Amer. Journ. of Physiol., 1901, v. 338, 357.
W. B. CANNON and H. F. DAY. Salivary Digestion in the Stomach. Amer.
Journ. of Physiol., 1903, ix. 396-416.
S. W. COLE. Contributions to our knowledge of the Action of Enzymes. Part I.
Jouru. of Physiol., 1904, xxx. 202-220.
W. P. MAY. The Innervation of the Sphincters and Musculature of the Stomach.
Jouru. of. Physiol., 1904, xxxi. 260-271.
P. B. HAWK. Influence of Rennin upon the Digestion of the Proteid Constituents
of Milk. Amer. Jouru. of Physiol., 1904, x. 37-46.
P. W. COBB. Contribution to our Knowledge of the Action of Pepsin with special
206 PHYSIOLOGY CHAP, in
Reference to its Quantitative Estimation. Amer. Journ. of Physiol., 1905,
xiii. 448-463.
J. C. HEMMETER. An Improved Operative Method of forming an Experimental
Accessory (Pawlow) Stomach in the Dog. Amer. Journ. of Physiol., 1906-7,
xvii. 321.
S. J. MELTZER and J. ATJER. Vagus Reflexes upon Oesophagus and Cardia. Brit.
Med. Journ., Dec. 22, 1906.
W. B. CANNON. The Motor Activities of the Stomach and Small Intestine after
Splanchnic and Vagus Section. Amer. Journ. of Physiol., 1906-7, xvii.
429.
L. B. MENDEL and F. P. UNDERBILL. Is the Saliva of the Dog Amylolytically
active? Journ. of Biol. Chem., 1907, iii. 135.
S. J. MELTZER. Secondary Peristalsis of the Oesophagus a Demonstration on a
Do<* with a Permanent Oesophageal Fistula. Proc. of the Soc. for Experim.
Biol. and Med., 1907, iv. 35.
W. B. CANNON. Oesophageal Peristalsis after Bilateral Vagotomy. Amer.
Journ. of Physiol., 1907, xix. 436.
W. B. CANNON. The Acid Control of the Pylorus. Amer. Journ. of Physiol.,
1907-8, xx. 283.
A. J. CARSLON and J. G. RYAN. Glucose in Saliva. Amer. Journ. of Physiol.,
1908, xxi. 301.
A. J. CARLSON and J. G. RYAN. The Diastase in Cat's Saliva. Amer. Journ. of
Physiol., 1908, xxii. 1.
C. H. NEILSON and P. 0. TERRY. The Effect of Potassium Iodide on the Activity
of Ptyalin. Amer. Journ. of Physiol., 1908, xxii. 43.
J. AUER. The Course of the Contraction Wave in the Stomach of the Rabbit.
Amer. Journ. of Physiol., 1908-9, xxiii. 165.
0. RIDDLE. The Rate of Digestion in Cold-blooded Vertebrates. The Influence
of Season and Temperature. Amer. Journ. of Physiol., 1909, xxiv. 447.
A. 0. SHAKLEE and S. J. MELTZER. The Destructive Effect of Shaking upon the
Proteolytic Ferments. Amer. Journ. of Physiol., 1909-10, xxv. 81.
J. AT/ER. The Effect of severing the Vagi or the Splanchnics or both upon
Gastric Motility in Rabbits. Amer. Journ. of Physiol., 1909-10, xxv. 334.
F. R. MILLER. On Gastric Sensation. Journ. of Physiol., 1910-11, xli. 409.
E. P. CATHCART. The Pre-pyloric Sphincter. Journ. of Physiol., 1911, xlii. 93.
CHAPTEE IV
MECHANICS AND CHEMISTRY OF DIGESTION IN THE INTESTINE
CONTENTS. — 1. Artificial digestion with the three intestinal secretions :
pancreatic juice, bile, succus entericus. 2. Mechanism of bile -excretion in the
intestine, and innervation of muscles of common bile-duct. 3. Natural digestion
of chyme in small intestine. 4. Putrefactive processes in the intestine. 5. Effects
of extensive resection of small intestine in animals and man. 6. Peristaltic move-
ments of intestine. 7. Central and peripheral innervalion. 8. Post-mortem auto-
digestion. Why it does not occur during life. Bibliography.
THE last chapter proves, as already stated, that the digestion
of food-stuffs in the mouth and stomach is very imperfect.
Contrary to earlier opinions, the acid pulp, known by the name
of Chyme, does not differ, chemically speaking, in its essentials from
the mass of the food-stuffs ingested, whether these be raw or
modified by cooking. The changes which the foods undergo in
the mouth are principally mechanical ; those which they undergo
in the stomach are principally antiseptic. But if not absolutely
indispensable to life, both these changes serve to prepare for and
to facilitate the true and complete digestion that takes place in
the small intestine, which is the subject of this chapter.
I. The acid chyme, after passing into the duodenum, en-
counters three alkaline secretions — pancreatic juice and bile in
the duodenum, succus entericus throughout the small intestine — by
which it is gradually neutralised. It is only in the last part of
the small intestine that the intestinal contents give an alkaline or
neutral reaction. The cause of the acidity of the intestinal contents
has been studied by many authors (Nencki and Zaleski, Moore and
Rockwood, Hemmeter, Gillespie, C. Foa, U. Lombroso, etc.).
According to most authorities the acid reaction of the intestinal
contents is due to a complex of factors, e.g. acidity of the gastric
juice, the fatty acids liberated from alimentary fats, the lactic acid
developed during digestion of the carbohydrates, the carbonic acid
formed by the action of stronger acids on the carbonates, etc.
C. Foa (1906), who undertook to control and confirm the
observations of various authors in regard to the actual and potential
reactions of the digestive secretions (which all present an almost
neutral actual reaction, the gastric juice alone giving a strongly
207
208 PHYSIOLOGY CHAP.
acid actual reaction), suggested that the acidity of the intestinal
contents might be due to the fact that the pancreatic juice and
the succus entericus were unable to neutralise the acidity of the
gastric juice. U. Lombroso, however, contemporaneously with
G. Rossi (1907), objected that in this case it would be, not the
actual, but the potential, reaction that must be considered, and
that the alkaline potential reaction of pancreatic juice is very
strong.
Foa (190S) accepted this criticism, but maintained that the
acid reaction of the intestinal contents was due solely to the
hydrochloric acid of the gastric juice. He observed that no free
hydrochloric acid was to be found in the filtrate of the gastric
and intestinal contents in the dog after a meal of flesh or niilk,
but only hydrochloric acid combined with proteins. Examination
of the filtrate, however, does not exactly account for the various
acid constituents of the intestinal contents, since we know that
the higher fatty acids to a large extent remain on the filter. We
cannot therefore attribute the acidity of the intestinal contents
solely to the combined hydrochloric acid, but must admit (par-
ticularly in view of the known data as to digestion and absorption
of fats which we are about to discuss) that all the other factors
above enumerated contribute to it.
In the preceding chapters we have already referred to the specific
enzymic activity of the various digestive secretions. It is now
time to determine more exactly the mode in which these various
factors in the complex problem of alimentary digestion come into
play — what favours and what thwarts their function — and how
that functional correlation is effected between the different secre-
tions which is necessary to the conversion of the food-stuffs into
the form that precedes their absorption.
In virtue of its enzymes, pancreatic juice acts, as we have seen,
on the three different groups of alimentary substances, viz. carbo-
hydrates, fats, and proteins. Its action in vitro can be studied
either with natural juice or with the extract of the gland.
The saccharifying action of pancreatic juice on starch (due to
amylopsiri) is similar to that of saliva, but much more energetic,
since at body-temperature (37-40° C.) it acts rapidly on boiled as
well as on raw starch. The rapidity of this conversion, and the
intensity of the effect, are astounding. Thus if pancreatic juice be
dropped into a test-tube containing starch paste stained with a
drop of tincture of iodine, the deep-blue colour disappears, and is
replaced by a violet -red (erythrodextriri), then by pink, until
finally it becomes colourless (achroodextriii). Minkowski suggested
a method for the rapid estimation of amylolytic activity, based
upon this sequence of readily observed phenomena.
According to Roberts, one part of amylopsin is able to convert
40,000 parts by weight of starch in less than a minute.
iv DIGESTION IN THE INTESTINE 209
Like saliva, the pancreatic juice does not convert the whole of
the starch into sugar, after it has passed through the intermediate
products of erythrodextrin and achroodextrin, but dextrin always
appears as one of the end-products, along with the sugar, which
mainly consists of maltose (von Mering and Musculus). Glycogen
undergoes the same conversion. Pancreatic juice also dissolves
cellulose and gum (Schmulewitsch)-— to a much larger extent in
herbivora than in man and in carnivora.
This digestive action of the pancreatic juice on the poly-
saccharides, which reduces them, with absorption of water, to
smaller and more soluble molecules, that can be easily absorbed
and assimilated, is of great importance in frugiverous birds, for
if the pancreatic secretion is drawn off externally, by a fistula, in
pigeons they die of progressive emaciation after a short time if
sugar be not administered, the giving of which delays their fate
(Langendorff).
Little is known of the origin of the zymogen of amylopsin, and
the factors which convert it into the enzyme. According to some
authors, the centro-acinar cells elaborate the zymogen, and the
epithelium of the ducts pours out a kinase by which it is activated.
Both entero-kinase and bile undoubtedly increase the amyloly tic
activity of the pancreatic juice (Pawlow). This action comes off
also in a slightly acid medium, which is very favourable to the
digestion of carbohydrates ; in fact, we have seen that the greater
part of the intestine presents an acid medium. According to
Griitzner, weak acids, as also 0'7 per cent sodium chloride, increase
the action of the amyloly tic enzyme, while more concentrated
solutions inhibit it, as do also alkaline salts, sulphates, alcohols,
chloroform, ether, thymol, etc.
After a few hours in the thermostat at 37° C. pancreatic juice
loses its amylolytic activity (also its other enzymic properties, the
lipolytic first, and the proteolytic more slowly).
The lipolytic action of pancreatic juice (due to steapsiri) is
exercised on the neutral fats, which are first emulsified per-
manently and completely, and then decomposed into glycerol and
fatty acids, with absorption of water. The power of emulsifying
fats is common to all alkaline fluids, but in a less perfect and less
stable degree, according to the quantity of free fatty acids which
Hoffmann finds to be present in all the fats. Alkali, in presence
of fatty acid, combines with it to form soap, which as Briicke
demonstrated, has the power of penetrating into neutral fat and
dividing it up into minute drops separated by a thin film of soap.
In order to prove that pancreatic juice really has the property
of decomposing neutral fats, they must first be freed from the
fatty acids which they contain by dissolving them in ether and
shaking, after which the ethereal layer is separated and slowly
evaporated, leaving a residue of perfectly neutral fat, which on
VOL. II P
210 PHYSIOLOGY CHAV.
dissolving iu alcohol no longer reddens litmus. On mixing this
purified fat with fresh, alkaline, pancreatic juice, and keeping the
mixture in the warm chamber at 37° C. with the addition of
a little litmus solution, the alkalinity gradually diminishes,
till the mixture finally gives an acid reaction owing to the
hydrolytic cleavage of the neutral fat, as first perceived by Ch.
Bernard and Berthelot. We shall presently see the great
importance of the lipolytic action of the pancreatic juice for the
utilisation of the ingested neutral fats.
On adding succus entericus to pancreatic juice the lipolytic
activity of the latter is a little increased. It is much reinforced
by the presence of bile, even in a small amount. According to
Bruno the lipolytic activity of pancreatic juice can be increased
20 times with bile. But if the experiment in vitro be pro-
longed beyond a certain time, the difference in activity between
the pancreatic juice alone, or with bile, diminishes. From the
teleological point of view it is an important fact that on adding
bile the pancreatic secretion retains its lipolytic activity much
longer.
The lipolytic activity of pancreatic juice is aided by a slightly
alkaline medium, but takes place in an acid medium also.
In order to measure the lipolytic action of pancreatic juice, a certain
quantity of the juice and of pure oil is placed in the thermostat at 37' C.,
and the quantity of ^n solution of alkali required to neutralise the fatty
acid formed is estimated.
The proteolytic action of pancreatic juice (due to trypsin) is
certainly its most important property. It acts on all proteins
with greater or less rapidity.
Eaw fibrin is more readily dissolved than other proteins, at
37-40° C., in 30 min. to 3 hrs. for large quantities, with a small
amount of trypsin, and without any symptom of putrefaction.
With other proteins that are more slowly digested (coagulated
albumin, cheese, meat, etc.), a little salicylic acid, or thymol,
chloroform, or ether (Ktihne) may be added to the extract to
exclude any trace of putrefaction, or, still better, a small quantity
of iodoform, which according to Vandevelde (1907) does not
interfere with the action of the enzyme.
Trypsin, unlike pepsin, digestion takes place both in an
alkaline and in a neutral or slightly acid medium. The optimum
of digestion occurs with an extract made alkaline with 0'3 per
cent solution of sodium carbonate. The addition of free mineral
acids, even in small quantities, entirely inhibits digestion. The
acids combined with metaproteins (at least in small quantities)
neither hinder, nor sensibly delay, digestion (Chittenden and
Cummins).
A further difference in the action of gastric and pancreatic
iv DIGESTION IN THE INTESTINE 211
juice is that with the latter boiled egg-white and other solid foods
are softened and split up without previous swelling, and that only
the muscular fibrils of meat are digested, while the connective
tissue and the collagenic tissues in general are left undigested
(Ludwig and Ogata).
The proteolytic activity of the pancreatic juice has been
estimated by different methods with results that are not always
comparable ; and there are conflicting opinions as to the laws by
which the digestive power of the pancreatic juice is developed.
According to Mett's method, trypsin digestion follows the law of
Schiitz and Borissow ; according to Gross, on the contrary, it is
in direct ratio with the concentration of the ferment.
Method of Gross (1907). One or two drops of the fluid to be examined
(or more if required) are placed in test-tubes containing 10-20 c.c. of a O'l per
cent solution of caseinogen and sodium carbonate. This is placed in the
thermostat, and samples taken at intervals of a few minutes of the mixture,
into which is dropped a 1 per cent solution of acetic acid. When the
mixture 110 longer becomes turbid, this shows that the caseinogen is entirely
decomposed.
Hedin's Method (1904). After making a digestion with protein of any
type, the liquid in which the digestion has taken place is precipitated with
an equal volume of a solution consisting of tannic acid 70 grms., acetic acid
500 grms., sodium chloride 100 grms., water 1000 grms. ; this is filtered, and
the nitrogen of the filtrate estimated by Kjeldahl's method.
The protein cleavage effected by trypsin is shown by the
work of Kiihne and his school (1867-93) to be very complicated.
Kiihne proved that it differs essentially from that effected by
pepsin, and may lead to a greater cleavage or disintegration of
the complex molecule of natural protein, independent of the
intestinal bacteria of putrefaction. The special text-books of
chemical physiology must be referred to for the study of all the
products into which proteins successively break up by the action
of trypsin. We must confine ourselves to stating that the first
direct products of cleavage are the secondary proteoses (deutero-
proteoses), and not primary proteoses (protoproteoses), as occurs in
pepsin digestion, and that the peptones are formed directly from
the deuteroproteoses. According to Kiihne pancreatic digestion
differs from gastric digestion, in that two kinds of peptones are
formed : a hemipeptone, which on the protracted action of trypsin
readily breaks up into leucine, tyrosine, aspartic acid, and other
products that are not exactly characterised, and an antipeptone
which resists the disintegrating action of trypsin, and can only
be decomposed into ammo-acids on boiling, with addition of dilute
sulphuric acid. The molecular aggregate of protein is thus com-
posed of two complex groups, the first of which splits up easily,
the other with difficulty ; both, however, contain nuclei of the
aromatic series as well as the fatty series. In the peptone of
gastric digestion, the two groups are still united, from which
212 PHYSIOLOGY CHAP.
Klihne gave it the name of amphopeptone. In pancreatic
digestion, on the contrary, the two groups of amphopeptone are
split up, and give rise to hemi- and anti-peptone.
There can be no doubt that hemipeptone breaks up under the
proteolytic action of trypsin, independent of any process of
putrefaction, for when pancreatic extract treated with salicylic
acid is digested in vitro for a long time, amino-acids and other
products of protein decomposition are constantly met with.
Before inquiring whether this advanced proteolytic process
takes place under physiological conditions in the intestine, as it
does in artificial digestions, we will examine the chemical action
of bile and succus entericus upon the food-stuffs.
The digestive action of bile in vitro is very insignificant. It
has no stronger solvent action on proteins than water. Some
authors (Klihne, v. Wittich, Giannuzzi, and G. Bufalini) have
recognised a slight diastatic action on starch from the bile of man
and some other mammals, which is probably due to small quantities
of ptyalin or amylopsin from the salivary glands or from the
pancreas, absorbed by the roots of the portal system, and recon-
ducted from the liver to the intestine with the bile.
The emulsifying (not lipolytic) action of the bile upon the
alimentary fats, which invariably contain a small amount
of free fatty acid (supra), is more important. As early as 1858
Marcet noted that if bile be added to fats mixed with oleic,
palmitic, or stearic acid, a part of the latter at once decomposes
the bile salts, and combines with the liberated alkalies to form
soaps, which produce a fine emulsion of neutral fats. When the
ordinary alimentary fats are employed, however, the emulsion
produced by the bile is rather coarse and unstable, owing to the
small amount of free acids which they contain.
In studying the digestive action of succus entericus in
vitro, either the glycerol extract of intestinal mucous membrane
or the juice that flows from a Thiry-Vella fistula after injection of
pilocarpine, may be employed, or the juice can be collected on small
sponges introduced into the loop of intestine. In these artificial
digestions, all trace of putrefaction must be avoided by adding a
few drops of alcoholic solution of thymol or salicylic acid (Masloff),
or still better iodoform (Vandevelde).
Provided the digestion of succus entericus in vitro proceeds
under aseptic conditions, it has been proved to exert no action on
protein, e.g. meat, egg-white, etc. On the other hand, 0. Cohnheirn
finds that it does act on proteoses and peptones, which are split
into amino-acids, owing to the specific proteolytic action of erepsin.
It further has the property of curdling milk by a process of casei-
fication, which, unlike that in the stomach, occurs in an alkaline
medium (Vella). This effect is due to chymosin, which is present
in small amounts in the succus entericus of certain animals.
iv DIGESTION IN THE INTESTINE 213
Boiled starch is rapidly converted into maltose. According to
Rohmann the glandular crypts of the jejunum secrete a juice that
has a more pronounced diastatic action than that from the crypts
of the ileum. Owing again to the action of invertin and lactase
enzymes peculiar to the succus entericus (though some hold that
they exist in minute quantities in pancreatic juice as well),
saccharose and lactose are hydrolysed and converted into mono-
saccharides, in which form the carbohydrate introduced with the
food is constantly present in the blood. Thus the succus entericus
completes the metamorphosis of this important group of food-
stuffs, the conversion of which commences in the mouth with the
action of the saliva, and is continued with increasing intensity in
the duodenum by the action of the pancreatic juice (Paschutin,
Eohmann, Bastianelli, Brown and Heron). Lastly the succus
entericus, from its alkalinity, co-operates with the bile and the
pancreatic juice in neutralising the chyme, in emulsifying the fats,
and perhaps also in their cleavage.
Taken as a whole the results of these experiments in vitro
upon the digestive action of the succus entericus secreted by the
small intestine bear out the general theory formulated by
Hermann — to the effect that digestion in the intestine converts the
greater part of the solid or colloidal, insoluble and iiidiffusible sub-
stances, represented by the protein compounds, the polysaccharides,
and the fats, into their respective decomposition or cleavage
products or units, which are soluble, readily diffusible, and easily
absorbed by the intestinal epithelium, e.g. peptones and amino-
acids, glucose, soaps, and free fatty acids.
II. In order to form a more adequate notion of the sum of the
chemical processes which go on in the intestine, it is necessary to
examine the changes that take place successively in the acid mass or
chyme in the different parts of the gut, owing to the synchronous
action of the three secretions whose activity we have been
separately considering, in so far as it can be detected from artificial
digestions of the natural food-stuffs.
But there is a preliminary question. In Chapter II. we saw
that the secretion of bile from the liver is continuous, unlike the
other digestive secretions, which take place only during digestion,
and cease entirely, or almost entirely, during abstinence (see pp.
134-138, Fig. 51). But while the secretion of bile is continuous,
its excretion or output into the duodenum is not continuous, but
periodic, and coincides exactly with that period of digestion in
which the acid chyme is spurted by rhythmical jets from the
stomach to the intestine. It is therefore evident that in the
intervals between digestion, the bile secreted by the liver must
all collect within the gall-bladder, which is a lateral diverticulum
of the excretory bile-ducts, where the bile becomes condensed by
absorption of water. What is the mechanism, by which the bile
P 1
214
PHYSIOLOGY
CHAP.
FIG. 72. — Dog's bile-duct obtained by
maceration with nitro-glycerin. Macro-
scopic view. (Oddi.) a, 6, plain
circular fibres of sphincter .of bile-duct
at the point at which it passes through
the coats of the intestine.
collects in the gall-bladder during abstinence, and is poured out
into the duodenum by the common bile-duct during digestion ?
In 1887 Oddi, with the object of determining the functional
importance of the gall-bladder, at-
tempted to produce a continuous
flow of bile into the intestine by
completely removing the gall-
bladder in dogs, an operation pre-
viously performed by Zambeccari, as
suggested by Galileo. The animals
operated on recovered quickly,
without exhibiting abnormal pheno-
mena of any significance. But the
sections made some time after si i owed
the hepatic duct, cystic duct, and
common bile-duct to be dilated to
twice or even three times their
normal calibre. The cystic duct, in
fact, seemed to be transformed into a reservoir for the bile, and
had the appearance of a newly formed gall-bladder. This experi-
ment has been utilised in surgery, since in cases of stones in the
gall-bladder (producing severe
colic) it is possible successfully
to open, empty, and excise the
gall - bladder abnormally dis-
tended by the presence of
calculi. To explain these re-
sults it must, of course, be
assumed that in animals de-
prived of their gall-bladder a
powerful obstacle is opposed to
the continuous outpouring of
bile, and promotes the marked
dilatation observed in the bile-
ducts.
This legitimate assumption
led Oddi directly to the dis-
covery of a special sphincter of
plain muscle, situated at the
duodenal end of the common
bile-duct, a sphincter which is
entirely independent of the
muscular coat of the intestine.
It is visible even to the naked eye in some animals (sheep, dog,
ox, pig), in which the bile-duct, before opening into the duodenum,
runs for a certain distance between the muscular coats of the
intestine (Fig. 72). In sheep and dogs, owing to the robust nature
FIG. 73. — Sections of intestine transverse to axis
of bile-duct, A, of sheep ; B, of man. Carmine
preparation. (Oddi.) a, b, sphincters of bile-
duct ; rf, muscular fibres of intestine, indepen-
dent of fibres of sphincter.
IV
DIGESTION IN THE INTESTINE
215
of the bundles that form the muscular hoop, and their independence
of the muscular coats of the intestine, it is very conspicuous under
the microscope, even with a low power, in sections parallel with
the long axis of the intestine (Fig. 73, A). In man, on the
contrary, owing to the delicacy of the muscle fibres, and the twist
in the lumen of the bile-duct, during its very brief passage through
the intestinal walls, the
sphincter-like arrangement
is less striking and char-
acteristic (Fig. 73, B.).
Oddifurther succeeded in
showing that the sphincter
of the bile-duct, like all
other sphincters, has a tone
of its own, which is able to
resist a column of 50 mm.
Hg ( = 675 mm. H20). This
explains why the sphincter
resists the pressure of the
bile, even when the gall-
bladder is full and dis-
tended, showing that its
tonic resistance exceeds the
normal secretory pressure of
bile by quite 475 mm. H20.
To complete his experi-
ments, Oddi also proved that
the tone of the sphincter of
the common bile-duct is
allied to the function of cer-
tain ganglia in its vicinity,
which have specific cyto-
logical characteristics by
which they are differentiated
from the plexuses of Auer-
bach and Meissner, of which
we shall speak later (Fig. 74).
According to Oddi, the presence of these ganglia explains why,
after separating the tract into which the bile-duct opens from
the remainder of the intestine, that orifice can remain closed
for a long while owing to the tonic -spastic contraction of the
sphincter.
In a later series of researches, Oddi succeeded in proving the
existence of a spinal centre, by which the tone of the sphincter of
the common bile-duct is regulated. In dogs this centre is
level, or at least in relation, with the first pair of lumbar nerves.
The afferent paths, according to Oddi, are represented by the
P2
FIG. 74.— Oblique section through dog's bile-duct, at
the angle of convergence between the thick muscular
coat of the intestine and the thin muscularis
mucosae, 35 diameters magnification. (Oddi.) a,
group of ganglion cells which regulate the tone of
the sphincter of the bile-duct ; b, muscular coat
of intestine ; 6, muscularis mucosae ; c, Oddi's
sphincter.
216 PHYSIOLOGY CHAP.
sensory nerves in general, and particularly by the centripetal
fibres of the vagus and sympathetic : the efferent by the anterior
roots of the first lumbar pair. The mechanism by which the flow
of bile into the intestine is brought about consists in a reflex
diminution of tone in the sphincter of the common bile-duct,
caused by the distension of the intestine and entrance of the acid
chyme from the stomach. It is, therefore, an inhibitory reflex,
discharged from a higher centre (of which the localisation is
entirely unknown), by which the tonic action of the lumbar centre
is suspended.
More minute researches into the contractility of the excretory
bile-ducts, by the graphic method, were carried out in Morat's
laboratory, and published by Doyon in 1893. According to Doyon
the contractility of these ducts is perfectly similar to that of all
other organs with plain muscle cells. They exhibit automatic,
rhythmic oscillations of tonus, similar to those above described for
the stomach. This rhythm can be seen in mammals, but is
particularly visible in birds (pigeons). After inoculation of pilo-
carpine, Oddi's sphincter enters into spastic contraction, and for a
long time resists the efflux of bile into the duodenum.
The great splanchnics, according to Doyon, contain the motor
nerves to the bile-ducts, since on stimulating them the whole of
the excretory biliary system contracts. It is possible that the
splanchnics receive fibres from the anterior roots of the first lumbar
nerves, and from Oddi's spinal centre. Dilatation of the common
bile-duct is usually obtained by reflex only, by excitation either of
the central end of the splanchnic (which causes dilatation of the
gall-bladder), or by the central end of the vagus (which produces
dilatation of Oddi's sphincter with simultaneous contraction of the
gall-bladder). Asphyxia causes constriction of all the bile passages,
as of the blood-vessels ; curarisation produces the opposite effect.
Injection of pilocarpine acts like asphyxia, atropine poisoning like
curare.
Bruno (1899), in Winogradsky's laboratory, with the object of
better determining the relations between biliary excretion and
digestion, excised in a dog the part of the duodenal wall which
contains the papilla of Vater, with the orifice of the common bile-
duct, and sutured it to the edges of the abdominal wound, after
stitching up the aperture into the intestine. On recovering from
the operation, this dog was for about a month the subject of many
interesting observations, from which the following conclusions may
be taken : —
(a) The flow of bile occurs only when the stomach contains
food, (b) The flow of bile commences after a latent period of 15
or more minutes, and continues till the stomach is completely
emptied of chyme, after which biliary excretion ceases, (c) Not
all food-stuffs are active, i.e. able reflexly to determine dilatation
iv DIGESTION IN THE INTESTINE 217
of Oddi's sphincter and outflow of bile. This is effected by fats,
proteins, and also by the extractives of meat. Carbohydrates seem
to have no definite action on biliary excretion, (d) The course of
biliary . excretion is more or less typical for the different classes of
food-stuffs. Generally speaking, it may be said that excretion is
due to the exciting action, not of the food-stuffs, but of their
digestive products. In fact, raw egg-white, which passes undigested
from the stomach to the intestine, is unable to produce excretion
of bile, even if it be introduced into the stomach in large amounts.
Boiled egg-white, on the other hand, which remains in the stomach
and is digested there, regularly excites a flow of bile, (e) Psychical
influences seern to produce no effect on the flow of bile. No bile
flows when the animal. is brought into the presence of foods, or
given milk while the cannula in the gastric fistula is kept open,
so that the food runs out of the stomach as fast as it flows in
(sham feeding). When, on the contrary, the gastric fistula is
closed, ingestion of milk is regularly followed by a flow of bile
after 12-17 minutes.
III. Various methods have been employed for studying natural
digestion in the intestine. The animal can be killed at different
periods of digestion to examine the contents of the several parts of
the intestine. Intestinal fistulae can be established in animals,
or pathological cases of intestinal fistula (anus preternaturalis) can
be utilised in man, both at the extreme end of the small intestine
and nearer the duodenum.
The fact that bile is inert when set to digest with proteins
gives no idea of its action on the same substances when they are
already acidified and partly digested by the gastric juice, nor of
the inhibitory or coadjuvant influence which it may exert on the
digestive power of the gastric juice, the pancreatic juice, or the
succus entericus, with which it necessarily mixes in the duodenum.
If bile be added to the chyme collected from the stomach of an
animal killed in full digestive activity, a precipitate is immediately
formed, even when the added bile is not sufficient to neutralise
the acidity of the mixture. Bernard was the first to draw the
attention of physiologists to the thick layer of caseous substance,
which adheres tenaciously to the villi of the duodenum of dogs
killed in full digestion. This layer results from the precipitation
of syntonin (metaprotein) and of the proteoses or propeptone,
by the alkali of the bile, the bile salts decomposing under the
action of the gastric juice. It is generally held that the gastric
acid combines with all the bases of the bile salts, throwing out
the syntonin, whilst the liberated bile acids combine with the
proteoses or propeptone, and precipitate them, the pepsin also
coming down mechanically (Briicke, Burkart, Moleschott, Almquist,
Hammarsten).
This process would result in the immediate suspension of
218 PHYSIOLOGY CHAP.
pepsin digestion, even before the acidity of the chyme had been
neutralised. But when the alkaline pancreatic juice and the
free alkali of the bile have neutralised the mixture and rendered
it faintly alkaline, the syntonin and propeptones thrown out dis-
solve again, and the pancreatic ferment once more acts energetic-
ally in the alkaline medium.
Bile therefore aids the pancreatic juice in its digestive function,
by checking peptic digestion in an acid medium, and promoting
pancreatic digestion in an alkaline or neutral medium.
From the work of Maly and Emich, it would seem that special
importance attaches to the taurocholic (not glycocholic) acid,
liberated by the action of the hydrochloric acid of the chyme. It
has the property of throwing out the albumin and the gelatin, on
which the pepsin also comes down in the precipitate, while neither
the albumin-peptone nor the gelatin-peptone is precipitated. In
consequence of this action of the taurocholic acid, the peptone
must therefore be separated in the duodenum from the proteins
that are little or not at all modified by the gastric juice ; the
peptone can at once be absorbed, the proteins, on the contrary,
must remain in the duodenum and be acted on by the pancreatic
juice. But, as we showed in the last chapter, the chyme which
passes from the stomach to the duodenum normally contains
either no peptones or hardly a trace of them; this process of
separation of peptone from the still incompletely digested proteins
is therefore of little importance.
That bile inhibits the enzymic action of pepsin, and thus
reduces or entirely suppresses the digestive function of the gastric
juice, is an undoubted fact which was confirmed by the work of
Bruno (1899), carried out by methods that leave nothing to be
desired in their accuracy. It is, however, very difficult to deter-
mine by what process this phenomenon comes to pass. To the
hypothesis that bile effects the destruction of pepsin, we may
oppose the fact that Hammarsten succeeded in isolating a pepsin
from gastric juice that had lost its digestive power by admixture
with bile, which on the addition of hydrochloric acid recovered
its digestive efficacy. It is possible that bile modifies proteins by
entering into combination with them, as Hammarsten thinks, and
thus rendering them indigestible by gastric juice; it is also
possible that it modifies the enzymic property of pepsin without
destroying it.
Bruno also points out that the bile which flows into the
intestine during the first hour of digestion exerts, caeteris paribus,
owing to its greater density, a more pronounced depressing action
on the gastric juice than the bile poured out in the succeeding
period. This still further emphasises the physiological function
of the bile, in destroying the enzymic action of the gastric juice in
favour of that of the pancreatic.
iv DIGESTION IN THE INTESTINE 219
It is probably for this purpose that there is at the close of
gastric digestion (particularly if rich in proteins, and therefore
more stimulating to pepsin secretion) an abundant reflux of bile
from the duodenum into the stomach. This fact, observed by
Pawlow and his pupils, has been studied in detail by Boldiretij
who brings out its constancy and modifications.
But the role of the bile is not confined to making possible
the digestive action of the pancreatic juice; it conspicuously
increases it, by promoting the enzymic activity of trypsin upon
proteins, of amylopsin upon starch and polysaccharides, of
steapsin upon fats. This is plain from the work of Martin,
Nencki, and others, and is confirmed and extended in the careful
experiments of Bruno, who compared the digestive power of a
mixture of pancreatic juice and bile in different proportions for
boiled protein, starch, and neutral fat.
The following are the most important of Bruno's conclusions : —
(a) Bile added to pancreatic juice raises its proteolytic activity
by 1'6S times on an average, i.e. it increases the solvent action on
t/ O ' A
protein, as if the pancreatic juice contained T68 times more
trypsin. The maximum reinforcing action of bile is obtained
when the quantity added to the pancreatic juice is not large.
(5) Bile added to pancreatic juice in the most favourable
proportions reinforces the amylolytic power of the latter to an
amount equal to increase of amylopsin by 2-43 times. But unlike
what has been stated for the action of bile upon trypsin, the
reinforcing action of bile on amylopsin increases in proportion as
the quantity of bile is greater.
(c) Bile also reinforces the lipolytic power of the pancreatic
juice, due to steapsin ; this action on the fat-splitting enzyme is
indeed, the most marked. The bile excreted after a meal of milk
is the most active ; it increases the lipolytic action of the pancreatic
juice 20 times. Even boiled bile is capable of reinforcing the
action of the lipolytic enzyme (although to a less extent).
These results justify the conclusion that the influence of bile
on pancreatic juice is precisely opposite to that which it exerts on
gastric juice. It is obvious that acquaintance with the action
of bile must throw not a little light on the work of digestion as
a whole, when it is accomplished under natural conditions in the
duodenum.
Careful study of the effects of intestinal acliolia in dogs
operated on by a complete biliary fistula, confirms the coadjuvant
action of bile in the processes of intestinal digestion ; at the same
time it shows the capacity of the body to compensate itself com-
pletely for total absence of bile in the intestine.
All the dogs operated on by Schwann with a complete biliary
fistula died shortly after; but Bidder and Schmidt discovered
that they could live a long while when fed more abundantly than
220 PHYSIOLOGY CHAP.
usual. It was, however, found that defaecation was infrequent
and difficult ; that the faeces assumed a fatty appearance, grey or
brown in colour, and had a putrid odour ; that much gas was
developed in the intestine and produced fetid flatulence ; and that
the expired air had a bad smell, both in fasting and after a meal.
In a word, dogs with a biliary fistula suffered owing to intestinal
acholia from exaggerated putrefaction in the intestine, which
caused progressive emaciation, and death. The autopsy showed
no particular lesion of the organs, such as would induce a fatal
result.
These observations gave rise to the conjecture that bile normally
exercises an anti-putrefactive action on nitrogenous food-stuffs.
But bile in itself is an effusion, that putrefies readily with much
evolution of gas (Giannuzzi and G. Bufalini) and development of
indole from the decomposition of the mucin (Ernest). We know,
however, that the bile salts are decomposed in the duodenum,
and that the free taurocholic acid actually exercises a certain anti-
putrefactive power (Lindeberger, Gley and Lambling), as does
also cholalic acid, which is a cleavage product of the former
(Bufalini, Albertoni, Limbourg).
The anti-putrefactive action of bile can also (it seems to us)
be regarded as an indirect effect of the excitatory action that it
exerts, more particularly by its free acids, upon the muscle fibres
of the intestine, increasing the peristaltic movements that serve to
expel the faeces. This is proved by the fact that intestinal acholia
produces constipation, on which the alimentary residues remain
longer in the bowel, and reach a more advanced stage of putre-
faction.
Lastly, the fact that in intestinal acholia there is almost always
a considerable quantity of fat that has escaped absorption, shows
that bile, besides favouring the digestion of fats, facilitates their
absorption. This fact depends essentially on the property of the
bile acids of dissolving the fa.tty acids liberated by the lipolytic
action of the steapsin. According to Marcet (1858), whose experi-
ments were subsequently confirmed by Moore and Rockwood, bile
acids, at body temperature, dissolve fatty acids to the amount of
2-6 per cent. These authors hold that the fatty acids are absorbed
in this state, and not in the form of emulsion. We shall return
to this interesting point. Meantime it may be added that accord-
ing to C. Voit, Rohmann, Fr. Miiller, the faeces in jaundice contain
55-78 per cent of the fats ingested, while in normal individuals
they contain only 7-10 per cent. The greater part of the fat in
the faeces is present in the form of free fatty acids, or combined
as soaps with lime and magnesia. Neurneister explains the
influence of bile on fat absorption by assuming that it is capable
of dissolving these otherwise insoluble soaps ; this does not, how-
ever, exclude the well-established power of bile acids to dissolve
iv DIGESTION IN THE INTESTINE 221
the fatty acids that have been liberated by the action of the
pancreatic steapsin.
Whatever the importance of this coadjuvant function of bile
in the processes of digestion and, more particularly, absorption in
the intestine, there is no need to exaggerate its significance, and
to hold that an animal with a complete and permanent fistula of
the gall-bladder must inevitably be considered moribund. The
intestine, like all other organs, possesses in a marked degree the
power of gradually adapting itself to deficiency of bile. Many
animals, when provided with a biliary fistula, as Barbera (1896)
observed, recover their original weight, and may live for a long
time in perfect health. This occurs with strong dogs operated on
in summer. Those, on the contrary, which are operated on in
winter and in very cold climates, grow more and more emaciated
and eventually perish from marasmus. The former pass the period
of adaptation to want of bile in a season at which there is little
need of fat as a thermogenic substance, and when the cold weather
comes they have established functional adaptation, and bear it
without disturbance of nutrition. In the latter, the disturbance
of intestinal functions due to the sudden deficit of bile occurs just
when there is great need of thermogenic substances to keep up
the equilibrium of the thermal balance, and for want of it they
consume their own tissues, lose flesh, and die of marasmus.
Digestion of proteins in vitro by pancreatic juice or extract
shows that the complex protein molecule may (independently,
according to Kiihne, of the processes of putrefaction) undergo
such decomposition and hydrolytic cleavage as to give rise to
amino-acids and other simple substances.
In many analyses of the intestinal contents of dogs fed with
flesh, however, Schmidt-Miihlheim finds either no tyrosine, leucine,
and aspartic acid, or merely traces of them. Nencki arrived at
the same result on examining the matter that escaped from a
fistula at the extremity of the small intestine in a woman. All
experimenters agree, again, in saying that hardly any peptones
occur in the intestinal contents at any period of digestion.
These differences in the results of artificial and of natural
digestion are readily explained on the assumption that the peptone
formed is rapidly decomposed, owing to the proteolytic enzyme of
the pancreatic juice, more particularly by the intervention of the
erepsin of the succus entericus, the crystallisable products that
arise (amino-acids) being promptly absorbed and utilised as fast
as they are formed. Confirmation of this important statement
will be found in the next chapter, when we shall study the
absorption of the digestive products of the alimentary proteins.
The functions of the succus entericus also stand out more
clearly and have more significance, when we pass from the results
of experiments in vitro to investigation of the physiological
222 PHYSIOLOGY CHAP.
conditions under which it acts in the intestine. We have shown
that it may co-operate in the emulsifying of fats, by partially
neutralising the acidity of the intestinal contents due to the
development of butyric and lactic acids, which are normally
present in the intestine in large quantities, owing to the fermenta-
tion of carbohydrates effected by the intestinal bacteria.
Bunge in this connection attributes great importance to the
large amount of sodium carbonate, which causes the succus
entericus to effervesce when treated with acids. The greater the
acidity of the intestinal contents, the more active, according to
Bunge, is the reflex secretion from the crypts of Lieberkiihu, as
already assumed by Thiry and Quincke.
He asserts that the intestinal mucous membrane tends rapidly
to neutralise the strong acids that are experimentally brought into
contact with it. Lombroso noted that when a solution of hydro-
chloric acid is passed into a short Vella's loop, its acidity is reduced
and practically neutralised in a few minutes. But if the acid be
combined with pepsin or protein, the neutralisation takes place
rather more slowly (U. Lombroso, C. Foa). How this neutralisa-
tion occurs is not exactly known. If we consider the quantity
of succus entericus excreted by the loop, and its potential alka-
linity, this is obviously much less than is required in vitro to
effect an equal reduction of acidity in the fluid in Vella's loop.
The same phenomenon does not occur when the higher fatty acids
are introduced into the loop instead of strong acids. In this case
the reduction of acidity is much less, and corresponds pretty
accurately with the potential alkalinity of the copious secretion
called out. We shall return to this interesting phenomenon as
demonstrated by Lombroso in our laboratory (1907-8), in treating
of fat absorption.
The sodium carbonate of succus entericus comes from the
decomposition of sodium chloride effected by the parietal cells of
the gastric glands, from which hydrochloric acid and sodium
carbonate are formed. The first is secreted, the second absorbed
by the glandular lymphatics, and passes into the blood. This
hypothesis is confirmed by the fact which Baldi (1885) established
in a number of experiments carried out in our laboratory : to wit,
that the blood examined during fasting is less alkaline than that
during gastric digestion, and that the greater alkalinity observed
during this period depends on the increased quantity of sodium
carbonate. The diminished acidity of the urine (Beaunis) and
the greater alkalinity of the bile (Gaglio) in gastric digestion
evidently result from the increase of sodium carbonate in the
blood, when the gastric glands are forming and secreting
hydrochloric acid. It therefore seems to us reasonable (although
direct experimental proof is still wanting) to admit that there
is a certain relation between the amount of hydrochloric acid
iv DIGESTION IN THE INTESTINE 223
secreted by the stomach and the amount of sodium carbonate
secreted by the intestine.
To this sodium carbonate Bunge assigns yet another function.
As -fast as it is secreted, it diffuses in the acid mass of the intes-
tinal contents, leading to a fresh formation of sodium chloride, with
evolution of free carbonic acid, which makes the whole mass
spongy and permeable to the pancreatic juice, thus assisting the
digestion or solution of the food-stuffs.
IV. To the chemical action of the secretions poured into the
intestine during digestion, must be added the constant action,
'even under normal conditions, of the Bacteria that inhabit the
intestine.
Their presence in the intestinal contents has been known ever
since the microscope was first applied to the phenomena of life
(Leeuwenhoek). The problem of determining their true physio-
logical significance is, however, beset with difficulties, and we can-
not at present claim that any definite theory has been arrived
at. We must here confine ourselves to a very general survey of
the subject.
There can be no doubt that the bacteria of the intestine pene-
trate from outside, along with the food, the fluids, the air that we
swallow; and that the development of the gases within the
intestines, as well as a considerable part of the substances that
compose the faeces, are due to the fermentations they excite, and
the further putrefactive decomposition which they produce in the
food-stuffs partially digested by the enzymes. We know, in fact,
that during the whole foetal period up to birth, there is no
fermentation in the intestine, which is sterile and destitute of
faeces. With the first frothy saliva, i.e. that mixed with air-
bubbles, swallowed with the milk by the new-born infant, the first
organic germs are introduced into its body. Many of these are
destroyed by the acidity of the gastric juice, but others pass into
the intestine, where they excite fermentative processes with
evolution of gas.
It is evident that the bacteria introduced with the food and
drink must be the same which act in the open air on the ferment-
able and putrescible matters. From the intestine of the new-born,
that have sucked milk, very few kinds of bacteria are, however,
secreted with the meconium in the 4th-10th hours after birth
(Escherich, 1875). All the other germs have been destroyed by
the bactericidal action of the gastric juice, or fail to find the
necessary conditions of their existence in the intestine of the
sucking infant.
In adults, too, although an enormous variety of germs con-
tinually pass by the mouth into the gastro-intestinal tube, the
gastric bacteria consist almost exclusively of Blastomycetes and
Sarcinae, organisms accustomed to live in an acid medium, and
224 PHYSIOLOGY CHAP.
the intestinal bacteria almost exclusively of the species Bacterium
coli and its varieties, to which the Bacillus mesenterictts (which
resembles that of typhoid) is frequently added. It is true, that
not a few authors (Macfadyen, Nencki and Sieber, Gessner,
Ciechowsky and Jaworsky), have described 7 species in the human
intestine under normal conditions, and Vignal 10 distinct species,
4 of which live in the mouth as well ; but in all probability many
of these bacteria must be regarded not as permanent but merely
as casual inhabitants of the intestine. Innumerable researches
of many workers in hygiene and pathology (Maggiora, Jensen,
MacWeeney, Laveran, Celli, and others) on the faeces not merely
of normal individuals, but also of persons affected with dysentery
and cholera nostras, have yielded only pure or almost pure cultures
of Bacterium coli and its varieties.
Bacterium coli -under the microscope appears as a bacillus, 1-5 /*
long, G'3-0'5 JM broad. In gelatin cultures the colony assumes the
form of a small, round, greyish-white protuberance. On studying
its metabolism in vitro, it has been found to produce partial
alcoholic fermentation of glucose, lactic fermentation of lactose,
and direct- cleavage of amygdalin into benzoic aldehyde and
hydrocyanic acid, with consumption of glucose. It does not
liquefy gelatin : it has the property of slowly coagulating milk
(in 4-5 days) and of slowly digesting fibrin, but not coagulated
egg-white ; lastly it gives off a strong and disagreeable smell of
putrefaction to the culture medium. It is, however, very probable
(infra) that under the special conditions of temperature and
environment in which their activity is manifested in the intestine,
these bacteria are capable of a more varied and energetic meta-
bolism, which is normally not pernicious, but may even be useful,
if not indispensable, to their host.
The cause of this relative constancy of the intestinal bacteria,
notwithstanding that the most varied species of microbes continually
penetrate into the digestive tube, presents an interesting problem.
That Blastoniycetes and Sarcinae alone can live normally in
the stomach is readily explained by the acidity of the medium ;
but why Bacterium coli and its allied species or varieties alone take
up their permanent abode in the intestine, is not easy to explain
(as Fermi noted) by the reaction of the environment, since this
should be suitable for the development of the most varied species
of microbes.
It is a fact that Bacterium coli is far less plentiful in the
air, in water, and in the soil than many other microbes, which
must therefore penetrate in much larger numbers into the digestive
canal (Schardinger). It is a fact that it is not the most resistant
to the action of the gastric juice, and that, on the other hand,
many microbes penetrate per anum, and are therefore not exposed
to the sterilising -action of the gastric juice (Escherich, W. Schild).
iv DIGESTION IN THE INTESTINE 225
It is a fact that it does not exhibit more rapid development and
greater vitality than other microbes, since in faeces exposed to the
air, in dead bodies, and in putrid matter in general, it gradually
diminishes and disappears, and succumbs in the fight with B.
pyogenes, B. liquefaciens, Vibrio rugula, and others (Dallemagne,
Bordas, Gilber, De Dominicis).
Fermi also excludes the hypothesis that the almost absolute
supremacy of B. coli in the intestine depends on the reaction of
the intestinal contents on the bile, on the enzymes of the
secretions, or the excreta separated by the mucous membrane
acting as an excretory organ, which might favour the development
of B. coli, and impede the development of other species. He
proved, indeed, that the proteolytic enzymes and bile exert no
action on microbes in general, and that many kinds of bacteria
nourish luxuriantly in the intestine post mortem, or on its
previously sterilised contents. He concludes that there must be
a reciprocal adaptation between the epithelia of the normal mucous
membrane and B. coli, a kind of symbiosis, while there is between
these epithelia and the other species of bacteria (even such as
develop more rapidly, and have a greater capacity for resistance
and higher fermentation power) a kind of antagonism which
obstructs their germination. Fermi finds confirmation of this
hypothesis in the fact that when the intestinal mucous membrane
is injured by different means, which cannot in any way affect the
intestinal bacteria, the latter are profoundly modified, B. coli being
reduced, with an invasion of numerous Vibrios, Protozoa, etc.
After peritoneal injections of typhoid toxin, Vibrios and also
Amoebae appear in the intestine of the guinea-pig, while B. coli is
reduced in number and its virulence increases (Sanarelli). When
venous stasis is artificially produced in the intestinal walls, the
virulence of B. coli increases in the injured loop (Klecki). The
same thing occurs in profound lesions of the mucous membrane
caused by cholera or dysenteric infections (Dreyfus, Lesage and
Macaigne, Jensen).
These and other similar facts demonstrate the adaptable
character or variable attributes of B. coli, which facilitate the
interpretation of certain physiological data that must now be
considered.
From our point of view the most important question is
whether the fermentative and putrefactive processes normally
effected by the intestinal microbes in the food-stuffs modified by
the digestive secretions, are or are not to be considered as a
second or complementary digestion, useful to the body inasmuch as it
completes the chemical work of the enzymes and utilises a greater
or less amount of alimentary material which would otherwise
be lost with the foetal dejecta.
The chemical processes which the microbes ' set up in the
VOL. II Q
226 PHYSIOLOGY CHAP.
contents of the intestine must be very complex, to judge from the
copious and dissimilar products that result. There can be no
doubt that the intestinal bacteria have a transforming action
on carbohydrates, on fats, and on proteins.
From carbohydrates there arise by fermentation, alcohol,
lactic, acetic, benzoic, succinic, butyric, and valerianic acid, with
development of carbonic acid gas, methane or marsh gas, and
hydrogen (Nencki). What is of greater importance — not merely
starch, but also cellulose can be digested and decomposed by
bacterial activity. Schmulewitsch observed that cellulose can be
partly digested by pancreatic juice, because after ligation of
Wirsung's duct the quantity of cellulose excreted with the faeces
is somewhat increased. But Tappeiner has shown that the greater
part of this conversion is effected by the intestinal microbes. On
taking weighed parts of the intestinal contents of freshly killed
animals, and dividing each into three samples, the first of which
is immediately set to digest as it is at body-temperature, the
second after sterilisation with an antiseptic, the third after boiling
—it is seen that the cellulose disappears only in the first sample.
If pieces of paper or cotton are placed in the mixture they are
dissolved. The importance of this is obvious, particularly for
those animals that live exclusively on vegetable matters, since
they are enabled not only to utilise a substance that is difficult
to digest, but also to render the nutritive substances enclosed in
the cuticle of cellulose accessible to the action of the enzymes.
In this connection it is interesting to note that if newly hatched
chickens are brought up on sterile food, they rapidly decrease in
weight, and die, like the controls that are kept fasting (Schottelius,
1902). The presence of intestinal microbes is therefore essential
to the life of these animals.
The acid reaction of the contents of the small intestine is due
principally to development of the organic acids above enumerated.
Neutral fats may break up in consequence of intestinal
putrefaction into glycerol and fatty acids, 'and the latter may
eventually undergo further cleavage, giving rise to the develop-
ment of simpler fatty acids. The steapsin of the pancreatic juice
is not capable of effecting this, so Landwehr assumed that the
capacity of splitting up the higher fatty acids belongs exclusively
to the bacteria, since, in his opinion, it ceases altogether in
perfectly aseptic, artificial digestions. But this view was shown
to be erroneous by Bruno's latest work, referred to above.
Still more important is the putrefactive action of the intestinal
bacteria upon proteins. This is not confined to splitting the large
protein molecule into proteoses, peptones, and amido-acids (leucine,
tyrosine, aspartic acid), as is the case with pancreatic digestions in
an aseptic medium in vitro (Kiihne, Salkowski, Salomon, Hiifner) ;
but the decomposition is carried further, to the development of
iv DIGESTION IN THE INTESTINE 227
nitrogenous bodies of the aromatic series, e.g. indole, scatole,
phenol, paracresol, phenyl-propionic acid, and other aromatic acids
(Nencki), with simultaneous development of gas (sulphuretted
hydrogen, carbonic acid, methane, hydrogen). When they act on
gelatin, the intestinal microbes also produce glycocoll or glycine
along with much leucine, ammonia, lactic acid, butyric acid, and
carbonic acid. Besides these well-defined chemical compounds,
the so-called ptomaines appear when the intestinal microbes are
cultivated on gelatin ; these are little-known alkaloids, which
often act as powerful toxins.1
It is obvious that if all these putrefactive decompositions of
protein occurred inside the intestine with the same intensity as
they do outside the body, they would not only fail to benefit the
organism but would be actively injurious, and mankind would be
in constant danger of fatal auto-intoxication. Maly expressed
the opinion that the limitation of our existence depends on a
series of continual and gradual modifications to which the body is
subject owing to the putrefactive processes of the intestine, and
repeats with Brieger, Homo non vivit quid putrescit. We believe
(as will presently be shown) that the true cause of natural death is
neither extrinsic, nor to be sought in the intestinal contents, but
is seated higher, i,e. in the intrinsic nature of the living protoplasm
and its metabolism. To Brieger 's apothegm we would oppose
the affirmation that Homo morietur quia vivit.
There must therefore be conditions in the normal state of the
intestine which tend to keep the putrefactive processes due to
microbes within narrow bounds, so that they shall subserve the
digestive functions of the secretory enzymes and not damage the
economy of the system. It is only necessary to assume that the
food-stuffs are absorbed as fast as they are sufficiently digested,
and carried away from the intestine, which removes them from
the further action of the bacteria. The acidity of the gastric
juice, again, fulfils an important bactericidal function in limiting
the entrance of germs into the intestine ; while the acid reaction
is also preserved in the jejunum and ileum, as far as the ileo-caecal
valve, not by hydrochloric acid, but by the organic acids developed
by the bacteria. These create a medium unfavourable to the
putrid decomposition of protein, and the excessive multiplication
of bacteria.
The observations made on man in cases of fistula of the upper
part of the small intestine confirm the importance of the com-
plementary digestive function accomplished by the intestinal
bacteria, as also the natural limitation of the putrefactive
processes which go on in the intestine.
1 The recent work of Dale and Barger and others has added considerably to our
knowledge of the origin and nature of these bodies, and their papers should be
consulted. (Journ. of Physiol., 1908-11.)
228 THYSIOLOGY CHAP.
We have already referred to a remarkable case of anus
preternaturalis in the upper part of the small intestine in a
woman. Busch, who described this case, was able to produce con-
siderable improvement in nutrition and increase of body weight,
by introducing food through the intestinal fistula where neither
bile nor pancreatic juice could penetrate. This case was cited by
Herzen in support of Schiff s theory, which endowed the succus
entericus with the power of digesting natural proteins. Now that
the impossibility of this assumption has been established, Busch's
observations are of still greater importance, because they show
that in the early stages of the putrefactive process the intestinal
bacteria are able to convert proteins into proteoses and peptones,
on which the digestive ferment, erepsin, can then act. Vizioli
repeated and confirmed the observations of Busch on another case
of fistula of the small intestine.
No less interesting are the studies of Macfadyen, Nencki and
Sieber, on another woman with a fistula in the lower part of the
small intestine. They showed that the bacteria confine them-
selves in this region to the decomposition of carbohydrates, and
that putrid decomposition of protein does not take place, or only
to a very limited extent. In fact, it was found impossible to
extract even the primary products of the putrid decomposition of
protein, leucine, and tyrosine from the contents of the small
intestine, probably because they are absorbed as fast as formed.
On the other hand, the acid reaction of the contents does show the
presence of organic acids derived from decomposition of carbo-
hydrates. Jakowski, on examining two other cases of intestinal
fistula in man, obtained fresh confirmation of these conclusions.
That the intestinal bacterial processes differ essentially from
those of ordinary putrefaction outside the body, may also be
concluded from the fact that normally, according to Brieger,
Baumann and Udransky, ptomaines are not found in the intestinal
contents, even when extracted some days after death. It
possibly the bile acids that make the intestines unsuited to the
development of the ptomaines.
Generally speaking, the presence of aromatic products (phenol,
indole, scatole) may be taken as the sign of putrefactive processes in
the intestine. Part of these products are absorbed and partially
oxidised : the indole is converted into in doxy 1, the scatole into
scatoxyl, and they are for the most part coupled with sulphuric
acid, reappearing in the urine as indoxyl and scatoxyl sulphuric
acid. The classical proof that the origin of these aromatic
substances depends exclusively on the life of the intestinal
bacteria is the fact of their invariable absence from the contents
of the foetal intestine and the meconium excreted by the
new-born.
V. In order the better to appreciate the functional importance
iv DIGESTION IN THE INTESTINE 229
of the small intestine, and particularly to determine the limits of
its adaptability, it is useful (as in the preceding chapter, in re
gastric digestion) to consider the effects of more or less extensive
resection of the several parts of the gut. Many of these operations
were initiated by surgeons, either on dogs with the simple object
of exploring in order to make clinical application of the results,
or on man with the therapeutic object of relieving cancer and
intestinal strictures consequent on strangulated hernia, cicatrised
constriction of the bowel, volvulus, traumatic rupture of the
small intestine, tumours of different sorts developed in the walls
of the intestine, and so on.
Senn was the first who undertook a series of experiments of
this kind on animals, and he came to the conclusion that the
resection of a third of the small intestine is a hazardous operation,
which results sooner or later in the death of the animal from
marasmus. Trzebicky (1894) continued the experiments, removing
first the upper portion of the jejunum, next the middle part of
the small intestine, then the extreme end of the ileum. In all
the dogs thus operated on, he found a diminution in the total
weight of the animal, proportional to the absolute or relative
length of intestine resected. When the excised loop does not
exceed certain limits, the loss of weight is arrested after a time,
and is succeeded by an increase which sometimes surpasses the
initial weight of the animal.
Unlike Senn, he found that dogs were well able to bear the
loss of half the small .intestine, the duodenum of course being
excluded. Even when these limits w'ere slightly exceeded the
animal could survive with a properly selected diet. Removal of
two-thirds of the gut, on the contrary, inevitably caused the death
of the animal, owing to insufficiency and disturbance of the
digestive function and absorption, as shown in obstinate diarrhoea,
followed by vomiting. The animal has a furious appetite, and
eats enormously, but still grows thinner from day to day, and
perishes of inanition. The autopsy shows typical death from
starvation, characterised especially by the almost total dis-
appearance of adipose tissue. In the intestine there is, moreover,
a conspicuous dilatation of the part lying above and below the
suture, but without compensatory hypertrophy of the intestinal
walls, as supposed by Senn. Trzebicky was eventually convinced
by his experiments that resection of the higher part of the small
intestine (jejunum) is more serious than that of the lower part
(ileum). Owing to its great physiological importance, this
conclusion deserves to be confirmed by further experiments under
conditions as far as possible identical and comparable. If
established, it would show that the functional value of the small
intestine for digestion decreases from above downwards, i.e. is
greatest in the duodenum, moderate in the jejunum, least in the
230 PHYSIOLOGY CHAP.
ileum, below which (large intestine) it is nil, as already pointed
out in discussing the digestive secretions (see p. 128).
Even more interesting from the physiological point of view is
the experiment in intestinal resection carried out on a bitch by
Monari and De Filippi (1892). They succeeded in keeping the
animal alive after extirpation of 1*90 m. of the small intestine.
During the first 13 days there was a progressive diminution in
weight, from which, however, the bitch recovered on a suitable
diet. Five months after the operation she was normally delivered
of 4 puppies, one of which was suckled for 3 weeks by the mother.
A year after the operation the animal was killed, when it was
found that only 25 cm. of the small intestine were left, i.e. ^
of the total initial length ! This observation shows that the
adaptability of the digestive functions is immense in a strong
subject, far in excess of what Senn and Trzebicky admitted.
Surgical operations on man in which short lengths of the small
intestine are successfully removed are common. On the other
hand, there are very few cases on record in which the patient has
survived the resection of long tracts of the bowel. A woman on
whom Bourn operated in 1884, by removing 1'37 m. of the
intestine, died of marasmus in 4 months. Kocher in 1886 saw a
man in good health from whom he had removed T60 m. of small
intestine. Four years later this patient showed no sign of gastro-
intestinal disturbances. In another with intestinal rupture from
a railway accident, Kocher removed 2-08 m. of small intestine.
The man recovered, but was subject to frequent diarrhoea.
Schlange in 1892 excised T35 m. small intestine in a female, who
was completely cured, with no sequelae from intestinal disturbance.
Trombetta (1883) operated on a woman suffering from sarcoma of
the small intestine. He cut away 1*10 m. along with the mesentery
and some hypertrophied lymph glands. The course of the malady
after this severe operation was favourable, and the patient was
cured.
The case described by Euggi in 1896 deserves more detailed
consideration. This is perhaps the most classical experiment that
physiologists can bring forward in man, to demonstrate the great
functional adaptability of the intestine where the patient combines
the favourable conditions of strength, youth, and perfect health of
the viscera. In a boy of 8, who had a large wound on the
abdomen at the level of the umbilicus, Ruggi, after two preliminary
operations in the hope of averting intestinal stricture by simply
dividing the tissues, was obliged to perform a third operation
13 days after the second,' the symptoms of intestinal stoppage
having again set in acutely. On making a large opening in
the abdomen, he saw that owing to an adhesive peritonitis the
greater part of the intestinal loops were knotted up into a huge
skein and could not be disentangled without freeing the loops
iv DIGESTION IN THE INTESTINE 231
from the mesentery. He was accordingly forced to cut away the
entire segment of intestine, which was covered with the exudates
produced by immobility of the intestine. When the operation
was complete he saw that the lower incision was 15 cm. above the
ileo-caecal valve ; the part removed, measured immediately after
the operation, was 3'30 m. long; obviously therefore the upper
incision must have been in the jejunum.
A series of measurements carried out on the dead adult subject
in the Anatomical Institute of Cracow showed that the length
of the small intestine may vary in man from a minimum
of 5 -60 m. to a maximum of 8*70 m. More than half the small
intestine therefore was removed in the boy on whom Ruggi
operated.
The post-operative history was unexpectedly favourable. After
a few days the patient was fully convalescent, but for at least 20
days he cried day and night from hunger, although he was allowed
a relatively large amount of food. At the end of a month, his
nutrition improved, and all bodily functions became regular,
defaecation included. It should be noted that the child had no
fever throughout the course of his illness.
A month after the operation Saggini made experiments (un-
fortunately incomplete) on 3 consecutive days, on this boy's
metabolism, from which the following positive data can be utilised.
In the 3 days of experiment the boy's weight increased 500 grms.,
as he was fed on an abundant diet, rich in nitrogenous and starchy
foods. The faeces only contained small quantities of nitrogenous
matters, carbohydrates, and fats, as compared with the amount
ingested in the food, showing that the processes of digestion,
absorption, and assimilation went on physiologically, in spite of the
serious anatomical loss of small intestine.
On repeating the same experiments on metabolism, 3 months
after the operation, for another 3 days, he found a marked
increase in weight as compared with the first experiments (1*7'600-
23'100 kgrms.), and an almost perfect equilibrium of balance
between intake and output, as deduced from the fact that during
the 3 days of investigation the boy's weight went neither up nor
down as a whole perceptibly. This shows that, in 3 months after
the operation, the child had made up the loss of weight due to
obstructed digestion during the period of illness prior to the
operation, and the enforced abstinence or scarcity of food in the
post-operative period.
Everything in this rare case of extensive resection of the small
intestine indicates that the functional adaptability of this organ,
which is the principal factor in digestion, is much greater than we
should suppose a priori.
VI. Owing to its muscular coats the intestine is an organ of
movement, with the office of gradually driving forward the chyme
232
PHYSIOLOGY
CHAP.
or alimentary pulp, in order to mix it with the digestive secretions,
to facilitate the absorption of the products of digestion, and finally
to expel the undigested and unabsorbed residues of food, along
with the excreta that collect in the gut.
The several parts of the intestine, morphologically speaking,
show a gradual differentiation, from which a correlative differentia-
tion of function may be argued. The duodenum is distinguished
not only by the absence of a mesentery, and by being only partially
covered with peritoneum, but also by presenting the widest and
most muscular part of the small intestine. Its total length varies
between 25 and 30 cm., its breadth from approximately 35 to 50 mm.
FIG. 75. — Auerbach's plexus between the two muscular coats of the intestine. Gold chloride
method. (Cadiat.)
The remainder of the small intestine, which has a mesentery, is
arbitrarily divided into jejunum (upper f) and ileum (lower f),
which have no distinct morphological boundaries. But the portion
between the commencement of the jejunum and the end of the
ileum (where the ileo-caecal valve is situated) gradually alters in
structure and appearance, so .that the two ends of the segment
can be readily distinguished. The jejunum is larger and more
muscular ; the ileum is narrower with thinner and paler coats, the
valvulae conniventes are smaller and gradually disappear at the
lower end, the villi are shorter, the groups of Peyer's patches
larger and more numerous. Owing to all these differential
characters, any part of the jejunum weighs more than a corre-
sponding portion of the ileum. The diameter of the jejunum is
about 3-25 cm., that of the ileum 2*60 cm. They vary consider-
ably in length, with age and with different individuals, as we have
iv DIGESTION IN THE INTESTINE 233
seen in another connection — probably in relation with the pre-
dominatingly vegetable or animal character of the usual diet.
The structure of the walls of the small intestine differs in no
essential from that of the oesophagus and stomach. The muscular
coat is composed of plain muscle. The longitudinal fibres form a
comparatively thin layer which becomes denser along the free
border of the intestine, the transverse or circular fibres are thicker
and more distinct : the first in contracting can only dilate and
shorten the intestinal tube (Exner) ; the second, on the contrary,
constrict and lengthen it. The longitudinal cells which thicken
along the free border of the intestine must stretch and distend
the numerous folds or convolutions.
FIG. 76.— Meissner's plexus, from submucous layer of intestine. Gold chloride method. (Cadiat.)
a, a, ganglia ; 6, b, cords of plexus ; c, small blood-vessel ; d, nerve filaments that accompany
the small artery.
A gangliated plexus lies between the two muscular coats, and
is in relation with the caeliac plexus, and branches of the vagus
and great splanchnic, and is known as the plexus myentericus or
plexus of Auerbach. It is principally composed of non-medullated
fibres, which give off a number of fine branches to the longitudinal
and circular muscle-cells (Fig. 75).
Other, larger branches pass through the circular bundles of fibres
to reach the submucous layer, where they form a second gangliated
plexus, the filaments of which are much finer than those of the
preceding ; this is called the plexus of Meissner (Fig. 76). From
this plexus, nerve fibres pass into the muscular layer of the
mucous membrane, breaking up into fibrils that ramify in the
proper tissue of the mucous coat and villi, and terminate, accord-
ing to Berkley, in small pear-shaped or globular dilatations.
234 PHYSIOLOGY CHAP.
On opening the abdomen of a recently killed animal, so as to
expose the intestines, they are seen to be the seat of writhing
or vermicular movements. At first these are hardly perceptible,
and are confined to the upper part of the small intestine, but they
soon become more ample and extend over its entire length to the
last section of the ileum, with decreasing vigour. They consist of
contractile waves propagated peristaltically, and preceded by waves
of dilatation ; the coils of intestine are displaced and move forward,
some being pushed down, while others come to the surface, sliding
one over the other. The irregularity and simultaneous appearance
of these vermicular movements in different parts of the intestine
confuse the observer, so that it is impossible to grasp the rhythm,
or the ascending or descending direction of the motion. After
reaching their maximum intensity, the waves gradually diminish,
and die out. But after the spontaneous movements have ceased,
it is possible to start them again by various stimuli. Haller
excited intestinal movements in a dog an hour after death, Colin
in the horse after about 50 minutes.
The movements observed in animals with an open abdomen,
such as Haller described, are, however, quite unlike the true
physiological phenomenon, i.e. the movements normally serving in
the intestine to propel and churn up the chyme, and to facilitate
intestinal absorption. They result from the abnormal conditions
of the intestine exposed to the air after the death of the animal,
when it becomes hyperaemic, cooled, and dried up.
If immediately after opening the animal's abdomen it is filled
with physiological saline, warmed to body-temperature : or better,
if the abdomen of a living rabbit be opened after fixing it in a
holder, and plunging the whole into a bath of the same saline
at 38° C., as first attempted by Sanders-Ezn and von Braam-
Houckgeest (1872), the duodenum and the jejunum alone exhibit
very slight movements, which can be separated into two groups,
according to whether or no they assist the progress of the
intestinal contents towards the large bowel : the former, known as
peristaltic movements, originate in a ring of constriction which
travels like a wave from one part of the intestine to the other ;
the latter, known as pendulum movements, exhibit a rhythmic
to-aud-fro motion of the single coils, which alternately contract and
expand — so that the contents are shifted about and thoroughly
mixed.
According to van Braam-Houckgeest, the longitudinal fibres
play an active part, even in the weakest peristaltic contractions,
for the advancing ring of constriction is immediately preceded by
a shortening and widening of the intestine which promotes the
advance of its^ contents towards the ileum. The length of the
annular wave of peristalsis varies greatly. If it traverses a short
distance, it is weak, and is frequently renewed. With stronger
iv DIGESTION IN THE INTESTINE 235
peristaltic movements (which are only seen in the filled and
distended jejunum), the ring of constriction travels like a rapidly
revolving wheel over long portions of the gut, driving the intestinal
contents forward tumultuously in the direction of the caecum. This
rapid, vigorous, and extensive wave of peristalsis was termed by
van Braam-Houckgeest the roll movement (Jiollbewegung).
Anti-peristaltic movements, i.e. movements in the direction of
the pylorus, are never observed under normal conditions. They
were formerly assumed to exist, as asserted by Engelmann in
1871, owing to the effect of mechanically exciting the intestine,
which produces a descending peristaltic and an ascending anti-
peristaltic wave. In living animals kept under the salt bath,
and also in the isolated loop with the Thiry-Vella method, anti-
peristaltic movements never occur. Fibini (1883) studied the
behaviour of a wax bolus introduced into a Vella's loop, and saw
that under normal conditions it travelled 1 cm. in 55 min. Eetro-
grade movements, due to the supposed antiperistalsis, never
occurred. On the other hand, increase of speed was noted when a
faradic stimulus was applied to the proximal end of the loop
(velocity = 1 cm. in 10 min.). Psychical influences (fear) also
increased the speed of the bolus.
Some clinicians, however, admit the existence of antiperistaltic
movements (at least under pathological conditions) to account for
faecal vomiting, consequent on stricture of the intestine ; but this
may also be caused by regurgitation due to the energetic action of
abdominal compression, independent of the intestinal contractions,
as already affirmed by van Swieten.
The experimental results of excising a more or less extensive
segment of gut, and then suturing it in the reverse direction, so
that the lower end is joined to the upper part of the intestine, and
the upper end to the lower part leading to the ileo-caecal valve,
harmonise with the theory that normal peristalsis is descending.
These remarkable experiments were first made by Mall, and
repeated by Kirstein (1889), then by Kauders (1893), and later
by Fasola and Sabbatani (1899). Many of the animals in whicli
this inversion of a loop of intestine was attempted died in the
first 2 days after the operation from purulent peritonitis,
caused by intestinal perforation owing to laceration at the
upper suture, where the intestinal contents accumulate and
stagnate. Kirstein, however, succeeded under special conditions
in keeping 2 dogs alive. Two cats survived with Kauders for
10-11 weeks. In the first week there was nothing abnormal
in their nutrition or defaecation; after that they began
to refuse food, and died with every symptom of slow starva-
tion. Out of 20 dogs operated on, Fasola and Sabbatani lost
in the first 2 days all in which the greater part of the small
intestine was reversed, as well as those in which the inverted
236 PHYSIOLOGY CHAP.
tract was comparatively short, but included the last portion of the
ileum. On the other hand, 4 dogs, in which a part of the small
intestine of varying lengths (60-110 cm.) had been reversed 15 cm.
above the ileo-caecal valve, survived for some time (5, 12, 15, 18
days). At the autopsy all these animals exhibited fusiform
distension of the intestine, the centre of which corresponded to the
upper suture.
More recently, two German surgeons, Enderlen and Hesse, on
repeating the same experiments with 3 dogs, arrived at different
results. Two of their dogs lived 73 days; another was killed
after 49 days. On faradic stimulation the inverted loop showed
peristaltic waves in the bucco-anal direction, i.e. in an opposite
(antiperistaltic) direction to that normal to the inverted loop.
They concluded that although normally there are no antiperis-
taltic movements in the gut, the reversed loop is capable of
adapting itself to the new conditions, and of inverting the direction
of its movements.
In Kirstein's 2 dogs (one of which was killed after 7
weeks, the other after 4 months) the important fact was
observed of a considerable thickening of the muscles of the
intestine, confined to the upper half of the dilated tract, to which
the lower end of the reversed loop was sutured. It should also be
noted that the dog killed after 4 months (although its nutrition
and defaecation were almost normal) was beginning to exhibit
emaciation, which might conceivably have continued until, like the
other dogs, it perished of marasmus, had Kirstein not been in
such haste to make his post-mortem examination.
Further experiments are needed before we can adequately
explain these phenomena. It seems to us, however, more than
probable that the fusiform dilatation of the intestine, as described
above, is the effect of accumulation there of the ingesta, secretions,
and intestinal gases, due to the resistance opposed by the reversed
loop, with its ascending peristaltic movements, to the passage of the
intestinal contents. This resistance (if the inverted part does not
adapt itself by reversing the normal direction of its movements)
can only be overcome by exaggerated descending peristalsis of the
upper part, as shown by the hypertrophy of its muscles, owing to
which there is passive dilatation of the first part of the reversed
loop, in which hypertrophy of the muscular coat is altogether
absent.
It has been attempted, from cases of intestinal fistula in man
and dogs, to determine the speed and force of the intestinal-
peristaltic movements ; but the results were very variable, as we
should expect on taking into account the different degrees of reple-
tion, varying character of the ingesta, and dissimilar strength of the
several parts of the gut. One important fact alone results from
these experiments, and harmonises perfectly with the anatomical
iv DIGESTION IN THE INTESTINE 23*7
and histological data, i.e. that both rate and force of the in-
testinal movements diminish regularly from duodenum to jejunum,
from jejunum to ileum.
The data as regards frequency and amplitude of the intestinal
movements in the opposite physiological states of sleep and waking,
fasting and digestion, agree fairly well. During sleep the motions,
such at least as are peristaltic, are much retarded or entirely
suspended. There is little difficulty in demonstrating this fact in
persons whose abdominal walls are thin owing to absence of
adipose tissue, or better in women who, as the result of previous
pregnancy, exhibit the so-called diastasis recti, along the linea
alba abdominalis. The observations of Busch upon the case above
referred to of fistula of the upper part of the jejunum, deserve
special consideration, because from the extreme tenuity of the
walls and the flattening of the abdomen of the patient, the move-
ments of the intestine were not merely palpable to the touch, but
could be seen as a progressive rise and fall of the abdominal wall.
During the greater part of the night all intestinal movement
ceased. During the day Busch noted periods of repose and
periods of intestinal activity, but with no regularity of rhythm
or duration. If the intestines were at rest before a meal, no
movement appeared immediately after,- but there might be a delay
of 10 or more minutes. On the other hand, long periods of
intestinal motor activity were not infrequently seen in the
fasting state, without any obvious reason.
In non-anaesthetised rabbits immersed in a bath of saline at
body temperature, the greater part of the intestine usually
remained at" rest, the duodenum and jejunum alone exhibiting
movements with an irregular rhythm. In this connection it
should be noted that, according to Pal (1890), the mere fact of
opening the abdomen suffices to determine reflex inhibition of the
intestinal movements.
These movements apparently become more vigorous and ample
during the outpouring of the digestive secretions, and of bile in
particular. According to Schiipbach (1907), however, bile has
no accelerating influence on^a bolus introduced into a Vella's loop
by the method indicated by Fubini. Eckhard, too, denies that
bile introduced into a coil of intestine in a rabbit immersed in
van . Braam-Houckgeest's bath has any accelerating effect on the
peristaltic motions. At times, however, without any apparent
reason, there is, now in one part of the small intestine, now in
another, a disappearance or reappearance of peristaltic motion,
which may assume the vigour and amplitude of the roll move-
ments described above. Generally speaking, it may be said that
the movements are both more frequent and more rapid in the
small than in the large intestine, and more lively and ample in the
duodenum and jejunum than in the ileum ; the former have a more
238 PHYSIOLOGY CHAP.
frequent rhythm (14-22 per minute), the latter a. slower rhythm
(12-18 per minute).
In dogs with intestinal fistulae near the valve of Bauhin,
Radziejeswski observed that the flow of the intestinal contents
through the fistula commenced 1 |-2| hours after a meal : that the
first expulsory movements occurred at intervals of 5-30 minutes ;
the later ones at greater intervals : and that some 6 hours after
the meal pauses or rests of many hours could be seen. There are
accordingly periods of activity and of repose, although it is not
possible to establish fixed data in regard to duration and rhythm
of the peristaltic motions. The results -of Braun and Lossnitzen
differed little.
The movements of the gut can be provoked or modified
artificially by mechanical, thermal, electrical, and chemical
stimuli ; as well as by the effects of hyperaemia and of
anaemia ; or by chemical agents introduced into the intestine.
The most important fact established by direct mechanical or
electrical stimulation of the intestine is that the contraction
excited at the point of stimulation spreads in both directions along
the bowel; in some species of animals, indeed, the curious fact
appears that the movement is propagated more extensively up-
wards than downwards, i.e. more in the antiperistaltic than in the
peristaltic direction (Engelmann). Nothnagel's experiments, how-
ever, show that the effect of excitation varies with the nature of
the stimulus. If a crystal of sodium chloride be applied to the
outer surface of the intestine, a contraction is produced which is
propagated upwards for some centimetres in the direction of the
pylorus ; a crystal of potassium chloride, on the contrary, produces
only a local spasm.
The dissimilar reaction of the longitudinal and the circular
muscle fibres to stimulation with the constant current is interest-
ing. Schillbach (1887) first noted that on bringing the kathode
into contact with the external surface of a loop of intestine a
localised contraction results, while on placing the anode in contact
the local contraction is transformed after a few seconds into
a peristaltic wave of contraction, which moves from the point
stimulated along the loop in both directions. Hillel Jafe* (1889)
confirmed this observation, and interpreted the primary effect of
the anodic closing stimulus as an effect of contraction of the
circular muscles of the muscular coat. Biedermann and Sinchovitz
(1889) extended these observations, and gave a better explanation
of their significance. According to these authors the effect of the
unipolar anodic closing stimulus is to produce a ring of constriction'
by the local contraction of the circular muscles. The effect of the
unipolar kathodic closing stimulus, on the contrary, is a slight
local contraction of the longitudinal muscles. Luderitz (1891)
also confirmed these data and their interpretation.
iv DIGESTION IN THE INTESTINE 239
It is evident that the character of the intestinal movements
differs from that of the oesophageal ; contraction of the intestine
from a local stimulus may spread under certain conditions in both
directions, although normally it progresses from the pylorus
towards the ileo-caecal valve ; the contraction of the oesophagus,
on the contrary, is always propagated from above downwards, in
the direction of the cardia. Another essential difference between
the movements of the oesophagus and those of the intestine
appears from the fact that the former continue to spread from
above downwards after transverse section of the gullet (Mosso) ;
the latter, on the contrary, are arrested at the edge of the section.
These, then, are true peristaltic motions, propagated through the
continuity of the tissue ; the movements of the oesophagus, on the
contrary, are (as we have seen) always propagated reflexly by
means of the cerebrospinal centres, and may therefore be termed
pseudo-peristaltic.
Conflicting opinions are held by various expefinienters in
regard to the influence of the vascular and circulatory conditions,
active hyperaemia, venous congestion, ischaemia, and asphyxia,
upon the intestinal movements. Nasse, S. Mayer, von Basch
contradicted Schiff 's statement that obstruction of the aorta evokes
or strengthens intestinal contractions ; they observed arrest for a
time, after which the movements returned with increased vigour.
Betz, van Braam-Houckgeest, and Mall, however, found that
anaemia inhibited all movements of the intestines. In asphyxia,
on the contrary, Mayer and von Basch found increase of the
intestinal movements.
The effect of heat on the movements of the gut is also interest-
ing, as shown by Claude Bernard's experiments. He placed the
quiescent intestine of a rabbit in a box with glass walls, at a
low temperature. As soon as a current of warm air was passed
through the box, visceral movements were exhibited, even before
the thermometer registered a rise of temperature. Horvath, too,
saw that the intestines of dogs, cats, rabbits, frogs, and guinea-pigs
remained quiescent between 0° and 19° C., and began to move above
that temperature.
Bayliss and Starling (1899), by means of the graphic method,
confirmed the statement that obstruction of the aorta arrests the
movements of the intestines. They inserted a balloon fastened
to a tube, with a recording apparatus, through a small longitudinal
incision in the loop, closing the slit with stitches, one of which is
taken round the tube. The capsule is distended with air under a
pressure of about 10 cm. water, after which the loop is returned
to the abdominal cavity. Under these conditions the intestine is
seen to be the seat of continuous rhythmic contractions, which are
fairly regular, and sweep down the intestine at a low rate. As
shown in Fig. 77, instantaneous occlusion of the aorta produces
240
PHYSIOLOGY
CHAP.
almost instantaneous arrest of the rhythmic movements, with
gradual decrease of muscular tonus. On removing the obstruction,
the viscus immediately gives a couple of beats, followed by a pause,
after which the rhythmic movements return in beats of growing
amplitude, while the volume of the intestine diminishes at the
same time, i.e. the tone of the muscles increases. This exagger-
ated return of intestinal activity is probably due to the great
vascular dilatation and hyperaemia of the viscus, consequent on
the prolonged anaemia which results from the occlusion of the
aorta.
VII. The movements of the intestine, like those of the heart,
FIG. 77. — Effect on rhythmic (systolic and diastolic) movements of intestine, of obstructing the
dog's abdominal aorta. Recorded with balloon method. (Bayliss and Starling.) CP, carotid
pressure ; I, contractions of intestine. At J, the aorta was blocked ; at ^ it was reopened.
can be carried out independent of the central nervous system.
This is proved by the fact that they continue (in a constantly
peristaltic form) in excised loops of intestine, under favourable
conditions of temperature and moisture (Salvioli). The question
whether these movements are automatic or reflex, and whether
they depend on a rhythmic property inherent in the muscle cells,
or on the ganglia of Auerbach's plexus with which the muscular
coats of the intestine are richly provided, has not been completely
solved by the data we possess at present.
The memoir published by Bayliss and Starling (1899) is of
great value in this connection. By an ingenious graphic method
they succeeded on dogs, anaesthetised principally with morphia, in
recording simultaneously the contractions of the circular coat and
the longitudinal coat of a loop of small intestine (exposed and
IV
DIGESTION IN THE INTESTINE
241
kept in a bath of warm saline). In this way they were able to
make a more exact analysis of the rhythmical movements
traced in the preceding figure (which probably correspond with
the pendular movements described by van Braam-Houckgeest)
and of the so-called peristaltic movements.
The most convenient way of recording the intestinal movements is by
the exploring rubber balloon, described above, which has been employed by
Q/M
FIG. 78.— Diagram of enterograph. (Bayliss and Starling.) a, a, brass plate, in which two steel
needles 6, c are fixed in a slot ; b can be shifted nearer to or farther from c by loosening its
fixing screw ; c is prolonged through the slot, and revolves round the axis d, d. The upper
end of c is fastened by a thread to the disc on the rubber of the tambour e, which communi-
cates by a tube /with a piston recorder. The lower ends of b and c are pierced with holes.
Through these holes pass fine threads which are carried by a needle through the outer layers
of the intestinal wall, and fastened. The muscle fibres running from b to c can only contract
by pulling c towards 6. This causes a movement of the upper end of c in the opposite direc-
tion, and a consequent pull on the membrane of the tambour, which is registered by the
piston recorder. The distance of e from c and the tension on the muscle fibres between b and
c can be regulated by means of the screw x.
various experimenters (Openchowski, Mislawski, Bunch, Courtade and
Guyon, etc.). This method, however, can only record the state of activity or
rest of the circular coat of the intestine.
In many cases it is advantageous to record the intestinal movements
without introducing any foreign body into the gut. With this object Bayliss
and Starling invented the instrument called the enterograph, as shown in
Fig. 78. Two separate eiiterographs may be fixed at right angles to one
another at the same point, so that one lever acts in the longitudinal, the
other in the transverse direction, in relation to^ the intestine, as shown in
VOL. II R
242 PHYSIOLOGY CHAP.
the schema of Fig. 79. With this arrangement it is possible to record
simultaneous tracings of the circular and the longitudinal coat of the
intestine.
The rhythmical (systolic and diastolic) pendular movements
are due to synchronous rhythmical contractions and expansions of
Upper . . Lower
FIG. 79. — Two enterographs placed at right angles on a segment of intestine, a, b, levers of
enterograpli recording contractions of longitudinal coat, c, d, levers of enterograph recording
contractions of circular coat. (Bayliss and Starling.)
both longitudinal and circular fibres (Fig. 80). They are more
or less visible in the whole coil of intestine, when exposed and
immured in the bath. They recur some 10-12 times per minute,
and course over the gut from above downwards at a velocity of
2-3 cm. per sec. (Fig. 81). Bayliss and Starling hold that these
movements are entirely myogenic in origin, i.e. due to automatic
Fio. 80.— Rhythmic contractions of intestine. (Bayliss and Starling.) A, systolic and diastolic
movements of intestine. Balloon method. Time marking =6 seconds. B, same movements as
A, recorded by two enterographs, showing synchronous activity of longitudinal (L) and
circular (C) muscle-fibres at same spot. The descending direction of the arrows indicates
direction of contraction.!
rhythmical activity inherent in the muscle cells, and that they
are propagated by muscular conduction, as assumed by Engelmann,
Gaskell, and Fano for cardiac rhythm.
In direct contradiction to this thesis we have Yanase's observa-
tions on the intestinal movements of embryo rabbits and the
human foetus in premature abortion. He found that the period
1 In all curves recorded by Bayliss and Starling with the balloon method,
contraction causes an upward movement of the lever. In the curves obtained by
means of the enterograph, contraction is signified by a downward movement.
Curves to be read from left to right. — TRANSLATOR.
iv DIGESTION IN THE INTESTINE 243
at which the first intestinal movements appeared, both in the
guinea-pig (26-27th day) and in man (77th day); is always later
than the appearance of nerve cells and nerve fibrils in the
muscular coat ; hence he upholds the neurogenic interpretation of
the intestinal movements.
The peristaltic movements are true co-ordinated reflex acts,
which depend on the mechanical (and chemical ?) stimuli operating
in the intestine. They are propagated by the local nervous
mechanisms (Auerbach's plexus), independent of the central or
extra-intestinal nervous system.
FIG. 81. — To show rate of propagated contractions. (Bayliss and Starling.) Two balloons 10 cm.
apart in a loop of intestine, cut at both ends. U.B=upper and LB=lower balloon. Time
marking = 6 seconds. Rate of propagation = 5 cm. per second, as shown by the delay in the
systoles 1, 2, 3, 4, 5, of the lower in respect of the upper tracing. (Ascending direction of
arrows shows direction of contraction.)
According to Bayliss and Starling, " the production of the
true peristaltic wave is dependent on the unvarying response of
the intestinal nervous mechanism to local stimulation." They
formulated the law of the intestine (which might better be
termed "law of intestinal peristalsis") as follows: "Local
stimulation of the gut produces excitation above and inhibition
below the excited spot." This confirms the observations of Colin
and van Braam-Houckgeest, from simple inspection, to the effect
that intestinal peristalsis always consists in a ring of constric-
tion preceded by a wave of relaxation, which forces the contents of
the viscus to pass along the intestine from above downwards.
Every point of the intestine is therefore subject to opposing
influences transmitted to it along its wall, viz. inhibitory impulses
244 PHYSIOLOGY CHAP.
from above, and auginentor or excitatory influences from below.
The activity of the intestinal muscles at any time will depend
on the relative influence of these two sets of impulses (Bayliss
and Starling).
Exner and his pupil A. Miiller made an interesting contribu-
tion to our knowledge of the reflex co-ordination of the intestinal
movements. Exner observed that when a pin was introduced
into a loop of intestine point forwards, it was regularly found
after a certain time to be inverted, i.e. head forward, point behind.
This mechanism of defence is effected by a complicated alternation
of relaxation and contraction of the muscle walls ; at the point
where the mucous membrane is pierced by the pin, the circular
coat relaxes, while the longitudinal contracts, so that a tumefac-
tion is formed which surrounds the pointed end of the pin.
At the same time a ring of constriction forms behind the pin,
so that it is first turned transversely to the loop, and subsequently
reversed, with the head foremost. Miiller found that this com-
plicated reflex mechanism acted just as well when the vagi and
the solar plexus were divided. It therefore seems as if this
mechanism were carried out by the local nervous mechanisms, i.e.
the plexuses of Meissner and Auerbach.
To illustrate the details of the ingenious theory of intestinal
peristalsis formulated by Bayliss and Starling, one of their most
important experiments may be quoted. In order to excite
peristalsis in an isolated loop of intestine, they insert, about one
inch from the upper end, a bolus made of cotton-wool covered
with vaseline. Shortly after putting in the bolus, the contractions
of the segment of intestine immediately above the bolus undergo
increasing augmentation, until the intestine at this point enters
into a strong tonic contraction. This presses the bolus onwards,
and as the bolus moves the ring of constriction follows it up
until it has expelled the bolus through the lower opening of
the coil. In some cases, after the bolus has been expelled, a
second slow peristaltic wave of contraction may pass from one
end of the coil to the other, as if to expel any detached portions
of the bolus that may be left behind. This progression occurs
only in one direction, from above downwards. If the bolus be
inserted from below and pushed up the gut it will be returned by
the way it has entered. If, however, the intestine is in good condi-
tion, the latter experiment becomes impossible. On attempting to
push up the lump of cotton-wool, the intestinal wall contracts
strongly above it and resists the upward passage of the bolus.
If two enterographs are placed at right angles to each other at
a point about the middle of a coil of intestine, so as to record
the contractions of both longitudinal and transverse coats, the
synchronous activity of the two coats is seen to be altered by the
passage of a bolus introduced from the upper end. Fig. 82 records
IV
DIGESTION IN THE INTESTINE
245
this passage. The beginning of the tracings (left) shows the
rhythmic synchronous contractions of the longitudinal and
circular muscle-fibres. At A a bolus made of cotton-wool coated
with vaseline was inserted by an opening into the intestine
4 A- inches above the enterographs. The contractions of the
circular coat cease instantly, and this inhibition is .accompanied
by a gradually increasing relaxation. There is some relaxation
of the longitudinal coat, but the rhythmic contractions do not
altogether cease. At B the bolus had arrived at the upper
longitudinal lever, and at C had passed this, and was directly
under the transverse enterograph or a little below it. At this point
a strong tonic contraction of both coats occurs, expelling the bolus
beyond the levers. This strong contraction passes off, to be
\ r \N
jj \T V ^
^-r\ \-— • . \
JV^V^V
FIG. 82.— Passage of a bolus down the intestine, as recorded synchronously by two enterographs
at right angles. Longitudinal (L), circular (C), coats. (Bayliss and Starling.) (Explanation
of letters in text.)
succeeded by another, which like the first is moving down the
intestine. In this second tonic wave the rhythmic contractions
are evident, superposed on the curve. After the passage of the
bolus there is shortening of the gut (increased tone of longitudinal
fibres), and the rhythmic contractions of each coat are no longer
synchronous.
Other valuable work has recently been carried out upon
isolated loops of intestine. Salvioli (1882) had described and
successfully applied an admirable technique for studying the
functions of parts of the intestine isolated from the animal. He
succeeded in nourishing these loops by artificial circulation of
blood serum through the superior mesenteric artery. The in-
testinal movements were recorded by very light levers placed in
different positions on the loop, so as to transmit the contractions
of both longitudinal and circular muscle-fibre".
This method, with slight modifications of detail, was revived
in 1899 by 0. Cohnheim, and in 1904 Magnus carried out a
246 PHYSIOLOGY CHAP.
series of experiments which led to interesting although somewhat
schematic results. He studied the intestinal movements of an
isolated loop, after stripping off (from within outwards) one or
more of its coats. He found that when the mucous membrane
is removed, the movements persist unaltered, and concluded that
they are not reflex, excited by stimuli from the mucous coat,
but are automatic in character. The movements also continue
after the submucous coat has been removed, from which he con-
cluded that they are independent of Meissner's plexus. Lastly,
on separating the inner (circular) from the outer (longitudinal)
muscular coat by a circular incision, so as to sever the inner layer
of fibres completely from Auerbach's plexus, he saw that the inner
(circular) coat remained motionless, while the outer (longitudinal)
coat still contracted rhythmically.
Magnus concluded that the intestinal movements are neuro-
genic not myogenic, automatic not reflex, and that the automatism
arises in the peripheral nerve centres of Auerbach's plexus. This
is a bold assumption. The violent removal of the mucous or
submucous coat cannot (as it seenis to us) be equivalent to
sequestration from peripheral stimuli, but rather increases them,
in consequence of the trauma due to the laceration of so many
afferent nerve fibres.
As regards the neurogenic character of the intestinal 'movements,
another assertion of Magnus also appears to us to be strained,
viz. that the conduction of excitation from one point to another
of a loop takes place along the muscular coat, without the co-
operation of Auerbach's plexus, nor still less of Meissner's.
Finally, the Eontgen rays, already applied by Guyon to the
study of gastric movements, have also been employed on the
intestine. Cannon, in particular, has carried out methodical
experiments by this method (see p. 194). He fed his experimental
animals (cats) on a diet mixed with bismuth sub-nitrate, which
intercepts the passage of the X-rays, and thus appears on the
photographic screen as a shadow. The animals were kept fasting
before the experiment, and the bowels cleared out with castor oil,
so that it became possible on living animals to follow the progress
of food down the alimentary canal. Cannon found that the food
was divided into many little segments in the small intestine,
owing to the rhythmic repetition of the pendular movements.
This segmentation of the food in a coil is repeated by the fusion
and redivision of adjacent segments, in a continuous process, so
that the churn ing-up of the chyme is actively promoted. In the
cat the rate of division into segments is about 30 divisions per
minute. From time to time a peristaltic wave drives the particles
forward, on which the process of segmentation recommences. When
the animals are made to react to painful stimuli, the intestinal
movements cease. During sleep, on the contrary, they continue.
IV
DIGESTION IN THE INTESTINE
247
These elegant experiments have been controlled and confirmed
by other workers, particularly by Wolff (1901-2) and Carvallo
(1907). The latter, at the Marey Institut in Paris, made some
interesting kinematographs of the progress of the food, from the
stomach through the intestines, in the frog.
Vd
FIG. 83. — Schema to show distribution of sympathetic and vagus in gastro-intestinal tube and
the posterior surface and great curvature of the stomach, with one or two fibres to the pancreas :
i tic uui ftixi lauii ui tiic ^au^iiciueu cuiu glvc uiigiu uu uiic gfonu BUUUIUIUUI ^uoy, aim ULUIG
splanchnic (PS), which contain the greater part of the sympathetic nerve to the intestine,
after traversing the solar plexus (Pl.s), the superior mesenteric plexus (Ms), the inferior (Mi),
and the hypogastric plexus Up).
i hypogastric plexus (Ip).
The peristaltic movements, which depend on Auerbach's plexus,
and are therefore exhibited in excised loops, are also under normal
conditions regulated and controlled by the extrinsic nerves which
reach the intestine from the cerebrospinal and sympathetic systems.
The afferent nerve paths run principally in the great splanchnics
and the vagi. The schema of Fig. 83 is intended to illustrate the
El
248 PHYSIOLOGY CHAP.
relations of these two iierves, by the chain of the sympathetic,
the solar plexus, the superior and inferior niesenteric plexus, and
the hypogastric plexus, with the various abdominal viscera, more
particularly the intestine.
Division of one or the other of these nerves, or even of both,
has at first no appreciable effect on the movements of the intestine ;
in a short time, however, a more or less conspicuous and persistent
exaggeration and disturbance ensues, owing to congestion of the
blood from the paralysis of the vessels.
Stimulation of the peripheral end of the splanchnic by the
experiments of Joh. Miiller, Ludwig, Nasse, and S. Mayer led to
no definite results. Pfliiger (1857) first showed that stimulation
of these nerves when the intestines were in vigorous motion
arrested the movements, in the same way as the vagus causes
arrest of the heart, i.e. by producing a relaxation. The same
effect can be obtained on exciting the spinal cord between the
5th and llth dorsal vertebrae. This observation (though it is
not always to be seen as clearly as could be desired) has been
confirmed by all subsequent workers. The phenomenon, as dis-
covered by Pfliiger, has, however, received different interpretations.
Schiff and Valentin, who saw that weak currents applied to the
splanchnic increased the intestinal movements, attributed the
arrest with strong currents to the exhaustion of the nerve.
S. Mayer and von Basch ascribed the standstill to ischaemia of
the intestinal walls, due to the vaso-constrictor fibres of the
splanchnic. Van Braam-Houckgeest, who at first adopted this
opinion, abandoned it later, on noting that even weak currents,
which fail to excite the vaso-constrictor fibres of the splanchnic,
do inhibit the movements of the intestine, contrary to the opinion
of Schiff and Valentin. Moreover, if the viscera of a rabbit are
exposed to the air till they become congested by vaso-motor
paralysis, stimulation of the splanchnics has no effect on the
blood-vessels, although the intestinal movements are inhibited
as in a normal animal. Jacobi stated, in confirmation of Pfliiger's
theory, that the inhibitory fibres of the splanchnic have a different
course from the vaso-constrictor fibres, and that section of the
nerves running from the suprarenals to the solar plexus annuls
the inhibitory action of the splanchnics, without interfering with
their vaso-constrictor effect. As regards excitation from the
spinal cord, Pfliiger's observation is contrary to that of Cl.
Bernard, who found that a transverse section, or the mechanical
stimulation (puncture) of the spinal cord above the origin of the
splanchnic, is followed by extremely energetic movements of the
intestines.
Ludwig and Kupfer, Schiff, Bechterew and Mislawsky, Bunch,
observed a motor effect in the intestines on stimulating the
splanchnics. The last observer, in 1898, obtained tracings from
iv DIGESTION IN THE INTESTINE 249
the intestine, which show that stimulation of the splanchnics in
some animals increases, in others inhibits muscular tonus ; in
others again there is inhibition with preliminary augmentation
of tone. Bunch concludes that the splanchnics contain fibres of
opposite functions, and that excitation of the nerves produces one
or the other effect, according as the inhibitory or the motor fibres
preponderate in the particular animal.
Ehrmann (1885), in work carried out in von Basch's laboratory,
suggested crossed innervation by the two kinds of fibres contained
in the splanchnics, and assumed that they were motor for the
longitudinal and inhibitory for the circular coat.
On the other hand, Courtade and Guy on (1897), in experiments
undertaken in Franc,ois-Franck's laboratory, state that in normal
FIG. 84.— Intestinal contractions. Balloon method. Intestine returned to abdomen. Shows
inhibitory effect of exciting peripheral end of cut splanchnics. (Bayliss and Starling.) The
white mark shows duration of excitation.
conditions of the intestine, excitation of the splanchnic produced
exactly the opposite effects, viz. contraction of the circular and
inhibition of the longitudinal coat. But they obtained the same
results as Ehrmann when the gut was in an abnormal state owing
to defective circulation and diminished tone of its walls. The
splanchnics must therefore contain motor and inhibitory fibres
for both layers of muscle.
Whatever interpretation be given to these conflicting results, it
is certain that under really physiological conditions the intestine,
on opening the abdomen of a dog in a warm saline bath, with intact
splanchnics, is absolutely motionless. Under these conditions
Bayliss and Starling (1899) find that division of the splanchnics
produces no immediate change in the intestines; but after
15 to 30 minutes they gradually become more active, the previously
motionless intestine begins to beat rhythmically, and any con-
tractions which were previously present become stronger and more
regular. The vessels become hyperaenric from vascular dilatation
250
PHYSIOLOGY
CHAP.
owing to paralysis of the vaso-constrictor fibres. Under normal
conditions, therefore, the splanchnics have a restraining influence
on the intestinal movements, which ceases after section of these
nerves.
This conclusion is strengthened by the result of stimulating
the peripheral end of the cut splanchnic immediately below the
diaphragm, after inserting a small exploring balloon into a loop of
intestine. As shown by Fig. 84, after a somewhat prolonged latent
period, there is a complete cessation of the rhythmic movements
with marked relaxation of the intestinal wall. When stimulation
ceases, there is a long after-effect, followed by gradual return of
the rhythmical movements, and increased tone of the wall.
Fio. 85.— Intestinal contractions. Balloon method. (Bayliss and Starling.) Stimulation of right
vagus in neck of dog, after atropin. /, inhibition ; CP, carotid pressure ; E, length of
excitation.
The influence of the vagus nerves on the movements of the
intestines has also been the subject of not a little controversy. E.
Weber, Budge, Ludwig and Kupfer, Engelmann with many others,
maintained that they have a motor action, and, notwithstanding
some differences of detail, it might be concluded from their results
that this was the exclusive effect. Bunch, however, observed in
certain rare cases out of a large number of experiments, that the
stimulation of the vagus may, like that of the splanchnic, produce
inhibition. Ott (1904), again, expressly declared that peripheral
stimulation of the vagi has an inhibitory effect. This harmonises
with the conclusions of Bayliss and Starling, which may be briefly
summarised.
According to these authors, no tonic influence on the intestines,
such as is apparently exercised by the splanchnic, can be attributed
to the vagus. Generally speaking, division of the vagi has no
iv DIGESTION IN THE INTESTINE 251
perceptible effect, either immediately or remotely, upon the move-
ments of the intestines.
Peripheral stimulation of the vagi (after division of both
splanchnics, as recommended by van Braam-Houckgeest and
Jacobi, so as to remove the tonic inhibitory impulses passing along
these nerves to the intestines) constantly produces temporary
diminution or cessation of the intestinal contractions, owing to the
cardiac inhibition which causes intestinal anaemia. If the inhi-
bition of cardiac activity is prevented by intravenous injection of
atropine, peripheral excitation of either vagus has no effect on the
intestine. But if the stimulation is repeated several times an
FIG. 86. — Tracing of intestinal rhythm as in Pig. 85, during a later stimulation of right vagus.
(Bayliss and Starling.) In this tracing the primary inhibitory effect is scarcely visible, while
the subsequent motor effect is strongly marked, and at one point produces a tonic spasm
which obliterates the intestine and compresses the balloon.
auguientor effect sets in, which increases with each stimulation.
The first effective stimulus is expressed in a temporary inhibition
which causes the dropping of one or two beats. In the succeed-
ing stimulations there is a double effect, i.e. the primary inhibition
is followed by an augmented rhythm ; the beats increase in
amplitude and frequency, and the relaxation is incomplete, so that
there is a great increase of muscular tone (Fig. 85). In many cases
the excitation is so pronounced that the lumen of the gut and
balloon are obliterated altogether by a strong tonic contraction
(Fig. 86). There seems to be no relation between the extent of the
inhibition and the amount of subsequent augmentation.
Bayliss and Starling concluded that the vagus nerves contain
two sets of fibres, inhibitory and augmentor. The inhibitory fibres
252 PHYSIOLOGY CHAP.
have a short latent period, the augmentor fibres a long latent
period. The action of the vagus on the intestines is therefore
twofold — an initial inhibition, followed by augmentation which
outlasts the excitation of the nerve.
Little is accurately known as to the localisation of the cerebro-
spinal centres of the nerves which influence the intestinal move-
ments. It is supposed that the spinal centres for the splanchnics
lie in the lower part of the cervical cord and the upper part of
the dorsal cord. But according to Ott inhibitory effects are also
obtained with stimulation of the optic thalami and the cerebral
peduncles. According to Budge and Valentin the intestinal
movements can also be excited by electrical stimulation of the
corpora quadrigemina and corpora striata ; according to Schiff, also
by that of the medulla oblongata, the annular protuberance, the
cerebral and cerebellar peduncles. Bochefontaine in Vulpian's
laboratory obtained movements of the intestines from dogs, with
faradic stimulation of certain points of the motor zone of the
cerebral cortex.
Bechterew and Mislawsky, and Bunch, tried to ascertain which
roots of the spinal nerves give off fibres to the intestines, by way
of the sympathetic cord. According to Bunch the fibres that run
to the splanchnics originate in the anterior roots of the sixth
thoracic and succeeding pairs of nerves, down to the second,
third, fourth, and fifth lumbar pair. On their way to the small
intestine they traverse the ramifications of the solar plexus, in the
ganglia of which they have a cell station.
The above discussion shows that the physiological theory of the
nerve centres and the central and peripheral, afferent or efferent,
nerve paths which regulate the intestinal movements, is still very
incomplete, doubtful in places, and fragmentary throughout.
VIII. Having reviewed the chemical phenomena of digestion
carried on in the stomach and intestines, we may opportunely
consider the physiological question proposed as early as 1772 by
Hunter, which has given much food for thought and experiment to
physiologists.
Hunter was the first who discovered, by dissection of a number
of subjects, the phenomenon of the softening of the wall of the
gastric fundus, which may lead to perforation, and the evacuation
of the contents of the stomach into the peritoneal cavity. He
noted particularly that this condition appeared most frequently,
not in persons who had died from disease, but in those who had
previously been healthy, and had come to a sudden death.
Having confirmed the fact for certain animals some time after
they had been killed, he interpreted it as a result of the digestion
effected by the gastric juice, which continued after death, and
dissolved not only the food-stuffs ingested, but the stomach
itself, after it had been deprived of the "vital principle." He
iv DIGESTION IN THE INTESTINE 253
concluded that digestion depends neither on the movements of the
stomach, nor on heat, but upon the gastric juices, which represent
the solvent for the food-stuffs introduced.
Spallanzani, who had already demonstrated digestion in vitro
when Hunter's memoir was published, recognised in the post-
mortem digestion of the gastric walls a confirmation of his
discovery. Accordingly he set himself enthusiastically to repeat
and vary the experiments of Hunter, but since he did not know
the right conditions of external temperature and the most favour-
able pre-mortem period of digestion, he never succeeded in obtain-
ing rupture of the stomach, but only a dissolution of the mucous
membrane near the fundus. From this he concluded that " the
abdominal sheaths of dead animals are less subject to the influence
of the gastric juices than the meat introduced into the interior
of the stomach." After feeding a fasting dog on some fragments
of another dog's stomach, killing it at once by strangulation,
and keeping the body in a warm place for nine hours, after which
he made the post-mortem, he writes as follows : " The dissolution of
these pieces of stomach was very marked, while nothing, on the
contrary, was seen in the walls of the stomach in the dog that had
been killed, save a slight maceration of the large end of the
stomach, owing to which the villous coat when touched with the
finger or other body is readily detached and dissolved." He
explains this fact on the assumption that the fragments of
stomach, " being free and floating in the visceral cavity, were
covered at every surface by the gastric juice, while the walls of the
stomach were subject to its action on the inner surface alone."
Another conclusion is implicit in these words, viz. that the
epithelium that clothes the mucous membrane of the stomach is
even after death more resistant to the solvent action of the gastric
juice than the muscular and serous coats of the gastric walls. He
convinced himself by his experiments as a whole of the fact
Hunter had discovered, of the post-mortem auto -digestion of the
stomach, and accepted his explanation. He only protested that
the phenomenon could not be independent of heat, " too many
facts being cited in this book which point infallibly to the opposite
conclusion."
In 1856 Pavy undertook to disprove the interpretation given
by Hunter of auto-digestion. Hunter, to support his position, had
propounded the following bold proposition : if it were possible to
introduce the hand into the stomach of a living animal, it would
resist digestion ; this would nob occur if the hand were severed
from the body. Pavy showed this to be a fallacy, for he found
that the hind limb of a living frog, and the ear of a live rabbit,
introduced into the stomach of a dog by gastric fistula, did not
escape the action of the digestive juice. Hence he concluded that
" vital force " is incapable of protecting the tissues either of cold-
254 PHYSIOLOGY CHAP.
blooded or of warm-blooded animals from the solvent power of the
gastric juice. Pavy's experiments were immediately confirmed by
Bernard, and in 1862 by Inzani and Lussana also.
Pavy explained the resistance of the living stomach to the
action of the gastric juice as follows. Since this' organ is highly
vascular, the alkalinity of the blood and lymph neutralises the
acidity of the gastric juice in proportion as the mucous membrane
is impregnated, and throws the pepsin out of court. The rabbit's
ear and the frog's leg, being poor in vessels, are incapable of
neutralising the juice, and become digested. In support of his
argument, Pavy succeeded in obtaining auto-digestion of certain
zones of the dog's stomach, in which he had interrupted the
circulation, a fact subsequently confirmed by Virchow, Panum,
and Cohnheim. We shall presently see the weak points of this
theory.
Bernard explained the phenomenon on the assumption that
the gastric mucosa is protected during life by its epithelium, " qui
se detruit et se renouvelle avec une grande facility ; de la, quand
la vie cesse, sa rapide alterabiliteV' Next to the epithelium he
attached great importance to the layer of mucus that varnishes the
stomach walls, so that " le sue gastrique se trouve comme dans une
vase de porcelaine." This same view was also adopted by Inzani
and Lussana, although, with the object of confirming it, they
destroyed or modified the protective epithelium of living animals
by various means, without observing any subsequent digestion of
the gastric walls.
Schiffs experiments (1868) plainly showed that the epithelium
is not indispensable to the integrity of the gastric mucosa. He
was unable to produce lesions of the mucous membrane in fistula-
dogs, after scratching off the epithelium of the stomach in places
with his nail. He kept a dog, in which he had produced an open
sore in the mucous membrane, alive for more than six weeks
without inducing auto-digestion of the stomach walls. He found,
indeed, that dead epithelium is also highly resistant to digestion,
for when he repeated Spallanzani's experiment of introducing
pieces of ox-stomach into the stomach of a dog, he found that the
muscular coat became soft and was partially digested, while the
epithelium, under the microscope, remained wholly intact.
Gaglio (1884) took up this interesting question in our
laboratory, starting from an acute criticism of Pavy. If livin
tissues are digested by the gastric juice, on what does the specia
immunity of the stomach depend ? Is it really a universal fac
that all living tissues save the stomach are attacked and digested
by the gastric juice ? Seeing that the pancreas secretes a juice
that has a peculiarly solvent action on proteins, which are
digested along the entire tract of the small intestine, why did
Pavy not ask himself why the pancreas and intestine also escaped
iv DIGESTION IN THE INTESTINE 255
auto-digestion during life ? He would at once have perceived the
inadequacy of his explanation, which applies to the stomach only,
and would have attacked the problem on wider grounds.
In the first place, does post-mortem auto-digestion take place
in the pancreas and the bowel ? Gaglio demonstrated this by
killing dogs 5 to 10 hours after digestion had commenced, by an
incision in the medulla oblongata, after which he placed the body
in an oven kept at a constant temperature of 39° C. by a d'Arsonval
regulator. On making sections, unmistakable signs of auto-
digestion appeared throughout the small intestine, the mucous
membrane of which was irregularly perforated, and showed
between half-digested loops of intestine parts that were more or
less intact. In the place of Peyer's patches he noted deep pits
with sharply marked walls, which resembled ulcerated plaques.
Beyond the lymph follicles of the open or necrosed plaques, he
found that the muscu]ar coats were more or less softened accord-
ing as the digestive process was more or less advanced, which
depended on the state of the intestinal loop, i.e. as filled with chyme,
or empty and distended with gas. The pancreas was softened,
reddish-brown in colour, with some parenchymatous effusions of
blood. Under the microscope it showed deformed gland cells, in
which the inner granular zone was no longer distinct from the
outer homogeneous zone, the one bulging out, the other being
reduced to detritus. Similar results were obtained from experi-
ments on fowls, guinea-pigs, and rabbits.
When Gaglio had killed the dog and placed it in the warm
chamber while the stomach was still full of food, he found that
the phenomena of auto-digestion were most marked in the stomach,
which might be almost entirely digested, and that the chyme
poured into the peritoneal cavity might begin to digest the
other viscera. But when the animal was killed 11 hours after an
abundant meal, he found the stomach perfectly empty without any
clear signs of auto-digestion, save for a more or less extensive
softening of the mucous membrane, while the inner wall of the
small intestine and pancreas exhibited phenomena of digestive
solution as described above.
The problem of auto-digestion cannot therefore be confined to
the stomach, but must be extended to the intestine and pancreas
also. Accordingly, the cause that prevents auto-digestion during
life is not peculiar to the stomach, but is probably common to
all organs on which the digestive juices containing proteolytic
enzymes take effect, both such as act in an acid medium (pepsin),
and such as digest in an alkaline medium (trypsin).
In order to see if the resistance to the action of the digestive
juices is common to other living organs as well, in analogy with
that of the stomach and intestine, Gaglio introduced active
gastric juice, or a very active glycerol extract of pancreas, into
256 PHYSIOLOGY CHAP.
the rabbit's bladder (after ligation of the ureters), into the vagina
and uterus of the same animal, and into the throat of the fowl
isolated between two oesophageal ligatures, and failed after 5
to 7 hours to detect any manifest sign of digestion in the
walls of these organs. He concluded that resistance to the action
of the digestive juices is not a property of the alimentary canal
alone, but is common to other living organs.
Even if Pavy's theory explained the resistance of these organs
to the action of gastric juice, it is wholly inadequate to explain
their resistance to that of the pancreatic juice. If we assume, on
the contrary, that these organs, which have a copious blood-supply,
are the seat of vigorous absorption through the blood and lymph
capillaries, it is easy to explain their resistance to the action of the
digestive juices, since these are absorbed and removed before they
can penetrate and saturate the tissues — a preliminary condition to
auto-digestion. That the proteolytic enzymes do not remain and
exhaust their activity in situ, but are reabsorbed, was demon-
strated by Brlicke, who found them in the urine, and also in the
muscles.
This theory of Gaglio certainly gives a simple and straight-
forward interpretation of the phenomena which he studied, taking
them as a whole ; but it is not sufficiently general to account for
other phenomena, subsequently brought to light by other workers.
None the less, credit is due to Gaglio for having prepared the
field for further investigations, by directing the attention of
physiologists to the post-mortem auto-digestion of the intestine and
pancreas,and proposing the problem of the non-digestion of these and
other organs during life, in a more comprehensive and logical form.
In continuation of Gaglio's experiments, Viola and Gaspardi
attempted to discover if the living spleen, a highly vascular organ,
is also refractory to the solvent action of the gastric juice. With
this object they introduced and fixed the spleen, with the whole
of its ueuro- vascular peduncle, through an aperture made in the
stomach of dogs and cats.
The animals thus operated on died or were killed after 12 to
48 hours, and the post-mortem showed complete absence of auto-
digestion. It should be noted that the animals after this crucial
operation either ate nothing or were fed on milk, which they
probably could not digest, since under such conditions the secretion
of gastric juice would be nil or scanty. No demonstrative value
can therefore attach to these results.
Contejean (1894) improved on the ingenious experiments of
Gaspardi and Viola by fixing an intestinal loop into the stomach
of dogs. In one of his most successful experiments, the dog was
killed 12 days after the operation, in which time twenty full meals
were digested. On section, it was found that the portion of
intestine bathed with gastric juice (4'5 cm. long, 1*5 cm. wide)
iv DIGESTION IN THE INTESTINE 257
showed four small perforations iu a longitudinal direction, through
which the intestinal mucosa was protruding so that it touched the
gastric mucous membrane at several points. From this and other
concordant results, Contejean concluded that the blood circulation,
by carrying away the digestive enzymes, is able to protect the
highly vascular organs from their solvent action ; but that this
protection is not unlimited, since after a certain time auto-digestion
sets in, and is arrested only when the parts exposed to contact with
the digestive fluids are once more covered, by regeneration, with a
mucous membrane and special epithelium.
The results obtained under admirable experimental conditions
by Contejean revived the question whether living protoplasm can
or cannot be attacked by enzymes, and in what the protective
action of the epithelia that clothe the mucous membrane consists ?
The new fact adduced by Contejean does not solve this problem,
because the tissue of the intestinal walls is digested by the gastric
juice in which, besides the ferment, the hydrochloric acid must be
reckoned with.
Matthes (1893-94), with the object of clearing up the patho-
genesis of gastric ulcers, performed a number of experiments on
dogs, and studied with the microscope and the unaided eye the
course of cicatrisation after circumscrib'ed or extensive ablations of
the gastric mucosa. He found that small losses of tissue were
immediately occluded by local muscular contraction, and that
ablations of even 6 cm. in diameter fill up promptly to two-thirds
their extent, while the exposed part does not increase nor grow
deeper by auto-digestion, but heals by a new formation of mucous
membrane clothed with epithelium. This was a fact already
known to pathologists, who are well aware that round ulcers of
the stomach may heal up without necessarily leading to perforation
by auto-digestion.
Matthes, by a number of other experiments, arrived at the
conclusion that the digestive enzymes are inactive towards living
tissues in a healthy state, and are therefore incapable of producing
auto -digestion 'in the body. But the hydrochloric acid of the
gastric juice acts as a protoplasmic toxin which first kills the
tissue cells, after which they are digested by the pepsin. So that
in the experiments of Pavy, Bernard, Lussana and Inzani,
Contejean, the phenomenon of the digestion of living tissues is
apparent only. They are not digested unless they have been
previously killed, or at least profoundly modified by the hydro-
chloric acid. Different animal tissues re-act differently to hydro-
chloric acid ; some are not altered by it at all ; some very little ;
others again are profoundly modified. According to Matthes,
this depends on an adaptation of the cells to the external con-
ditions under which they live and function. The resistance of
the walls of the stomach to the toxic action of the hydrochloric
VOL. II S
258 PHYSIOLOGY CHAP.
acid must primarily be referred to the constitution of its epithelial
cells. Yet it seems to us essential to recognise that the sub-
epithelial tissues also present a considerable resistance, otherwise
we cannot explain why extensive interruptions in the continuity
of the mucous coat can be repaired before the tissue is digested.
Even before Matthes, and independent of him, this problem
was treated in a yet more general form by Fermi (1890-95), who
brought new evidence to support the thesis that living protoplasm
cannot lie attacked by the proteolytic enzymes. He called attention
to the bacteria and animal and vegetable parasites that swarm in
the alimentary canal, referring to facts that were already partly
known, but that no one had thought of invoking iu connection
with this subject.
Fermi observes that Hyphomycetes and Blastornycetes live and
multiply in both natural and artificial gastric juice, and modify
its reaction and digestive activity ; that trypsin in alkaline
solution is inactive in vitro to the whole class of Schizomycetes,
which, indeed, live and multiply upon it ; that Amoebae consisting
of naked protoplasm are neither digested by trypsin in vitro nor
in the intestine ; that the seeds of Graminaceae and Leguminosae
flourish and germinate well in sterilised solutions of active trypsin ;
that, lastly, worms and insect larvae immersed in solutions of
trypsin are in no way attacked, and that Lumbricidae and
Ascaridae find the proper medium for their development and
reproduction in the intestines of animals.
Fermi further notes that sterilised active trypsin can be
injected in strong and repeated doses (2 grrns. per diem for a week)
under the skin of living guinea-pigs, without producing any
symptom of digestion. It is not absorbed, but is destroyed in situ
by the living protoplasm of the tissues. Ten minutes after
injection in the guinea-pig, and five hours after in the frog, it is
no longer possible to find a trace of trypsin anywhere in the body,
even with the highly sensitive gelatin method — gelatin, according
to Fermi, being liquefied even by the most dilute solutions of
trypsin. When mixed with freshly minced organs of newly killed
animals, the trypsin disappears completely after 24 hours. This
is not the case when the organs have been previously boiled.
The so-called digestion of living tissues is due to the deleterious
action of hydrochloric acid, which alters or kills the cells prior to
their digestion by pepsin. This action is promoted by temperature.
In effect the tissues of a living frog resist the solvent action of
the gastric juice in vitro at 15-20° C. ; while they are digested at
the temperature of 38° C. at which Pavy, Bernard, and others
experimented. The cells of the gastric mucous membrane are
specialised cells, adapted for living in the presence of hydrochloric
acid, like the cells of the sulphuric acid glands of certain
Gasteropods which tolerate this acid in 4 per cent solutions, like
iv DIGESTION IN THE INTESTINE 259
the cells of Blastomycetes and Hyphomycetes which develop in
gastric juice, like the cells of highly acid plant organs which
perish in an alkaline medium.
An experimental illustration of the theoretical conclusions of
Fermi and Matthes was put forward by one of Eredericq's pupils,
Paul Otte, in 1896. He sought to elucidate the comparative
value of the epithelium as a protective organ of the subjacent
tissue. With this object he isolated a loop of intestine in the
dog, washed it with physiological saline, and then introduced
active gastric, or equally active pancreatic juice, kept in the
cavity by means of two ligatures at the extremities of the loop,
and stitched up the abdominal wall. After 5 to 8 hours the
animal was killed, and the changes produced by the digestive
juices in the loop examined, either by simple inspection or with
the microscope. His results briefly described are as follows : —
(a) Neither pancreatic nor gastric juice is capable of attacking
the normal mucous membrane of the intestine, although this is
not, like the gastric mucous membrane, inured to the presence
of free hydrochloric acid. This result is identical with that
obtained by Gaglio on the bladder, and probably lends itself to
the same interpretation.
(&) If before introducing one or the other of the digestive
juices, the loop of intestine is washed for a short, time with 2 per
cent silver nitrate solution, and then with 06 per cent sodium
chloride, no digestive alteration is produced, although the epi-
thelium which covers the tips of the villi is altered and killed
by the action of the caustic. Nor does the injection of 0'05 per
cent sodium fluoride solution produce any sign of digestion in the
loop, although it completely alters the osmotic and absorbent
power of the mucosa without destroying the epithelium. These
results can be explained neither by the theory of Gaglio nor by
that which attributes an exclusively protective function to the
epithelium.
(c) If before introducing the digestive fluids into the loop, the
blood-vessels running to it are tied, auto-digestive phenomena
make their appearance rapidly. Since mere ligation of the vessels,
without introducing digestive fluids, produces no clear symptoms
of necrobiosis in the intestinal epithelium after eight hours, we
are forced to conclude that ligation, by altering the nutrition of
the mucosa, disposes it to become saturated with the solvent fluids
to which it is normally refractory. The auto-digestive lesions
common in the stomach and intestine of patients who have died
after a long illness, are also due to the bad nutrition and enfeebled
resistance of the mucous membrane to the digestive action of the
pancreatic juice.
As a whole, the phenomena which we have been discussing
show the resistance of the living protoplasm to the attacks of the
260 PHYSIOLOGY CHAP.
intestinal enzymes. This property is not peculiar to the cells of
the gastric and intestinal walls, but is probably common to all
living cells. Thus after much research (which has certainly not
been useless, and is highly suggestive) the old doctrine of Hunter,
emphasised by Spallanzani, emerges, rehabilitated, from the attacks
of its opponents. Hunter's theory cannot, of course, be taken in its
original mystical and allegorical form, which is the habitual
disguise of such scientific intuitions as outrun experiment.
Fundamentally it amounts to this : the cause of the resistance of
living protoplasm to the action of the digestive enzymes must
be sought not in extrinsic but in intrinsic conditions, i.e. in its
intimate constitution.
More recently Weinland (1902), starting from the fact that
the Ascarids find in the intestine the medium best suited to their
existence, has attempted to determine the intrinsic conditions that
render them refractory to the proteolytic action of trypsin. On
rubbing up these intestinal worms into a pulp, with successive
alcoholic extractions, he obtained a substance which he termed
anti-ferment, because it has the property of protecting the proteins
from the proteolytic action of pepsin or trypsin. According to
other work of Weinland, there is within the interior of the
epithelial cells of the gastric and intestinal mucosa an anti-ferment
with similar action to that of the Ascarids. This would explain
the special resistance of the epithelium to auto-digestion, not only
during life, but also to some extent after death. How then are
we to explain the resistance to auto-digestion during life in those
tissue cells which are digested after death ? It is not enough to
assume with Weinland that they probably contain an anti-ferment ;
it is necessary to prove that the latter is destroyed at the moment
life ceases. Such a demonstration is absolutely impossible, because
the method of extracting the anti-ferment begins by killing the
tissues in reducing them to pulp ; and if this pulp contains the
anti-ferment, as affirmed by Weinland, this would imply that it is
not unstable, but persists after the death of the cells. The true
solution of this problem would evidently solve the enigma of life
and death !
BIBLIOGRAPHY
For General Literature see Bibliographies at the end of Chapters II. and III.
Excretion of Bile : —
DOYON. Arch, de phys. norm, et path., 1883-84.
BRUNO. Arch, des sciences biologiques de St. Petersbourg, 1889. (This admirable
work also gives an exhaustive discussion of the digestive properties of bile.)
ODDI. Di una speciale disposizioue di sfintere allo sbocco del coledoco. Perugia,
1887. Monitore zoologico italiano, v., 1894.
The Literature of Intestinal Bacteriology and its Physiological Bearings is
reviewed in : —
FERMI. Policlinico, iii., 1896.
iv DIGESTION IN THE INTESTINE 261
The Literature relating to the Effects of Extensive Resection of Intestines in
Animals and Man is reviewed in : —
RUGGI. Policlinico, iii., 1896.
Theory of Intestinal Movements : —
PFLUGER. Ueber d. Hemmungsnervensystem fur die peristalt. Beweg. d. Darme.
Berlin, 1857.
BUSCH. Virchow's Archiv, 1858.
NASSE. Beitrage zur Phys. der Darbewegung. Leipzig, 1866.
S. MAYER and v. BASCH. Wien. Sitzungsber. Ixii., 1870.
ENGELMANN. Pfliiger's Arcliiv, ii., 1869 ; iv., 1871.
VAN BRAAM-HOUCKGEEST. Ibidem, vi., 1872 ; viii., 1874.
G. SALVIOLI. Du Bois-Reymond's Archiv, 1880. Archivio per le scienze mediche,
v., 1882.
NOTHNAGEL. Zeitschr. f. klin. Med. vi., 1882. Phys. und Path, des Darms.
Berlin, 1884.
EHRMANN. Wien. nied. Jahresb., 1885.
BETZ. Zeitschrift f. rat. Medicin, N. F. i., 1851.
CL. BERNARD. Le9ons sur la chaleur animale, 1866.
SCHILLBACH. Virchow's Archiv, cix., 1887.
KIRSTEIN. Deutsche med. Wochenschrift, 1889.
BECHTEREW and MISLAWSKY. Du Bois-Reymond's Archiv, Suppl., 1889.
SABBATANI and FASOLA. R. Accad. di medicinadi Torino, 1890. Lo Sperimentale,
54, 1900.
S. FUBINI. Moleschott's Untersuchungen, xiv.', 1891.
JACOBI. Archiv fur exp. Path, und Pharm. xxix., 1892.
KAUDERS. Centralbl. fiir Phys. vii., 1893.
P. GRUTZNER. D. medicinische Wochenschrift, 1893.
G. PAL. Wiener klin. Wochenschrift, No. 51, 1893.
COURTADE and GUYON. Archives de physiologic, 1897.
BUNCH. Journal of Physiology, xxii., 1898.
COHNHEIM. Zeitschrift f. Biologie, xxxii., 1899.
BAYLISS and STARLING. Journal of Physiology, xxiv., 1899 ; xxvi., 1901.
BAINTON. Frorieps notizen, June, 198.
ENDERLEN and HESSE, Zeitschrift f. Chirurgie, lix. , 1901.
A. EXNER. Pfliiger's Archiv, Ixxxix. , 1902.
STARLING. Ergebnisse d. Physiologie, i., 1902.
I. SIMON. Lo Sperimentale, Ivii., 1903.
A. MiiLLER. Pfliiger's Archiv, cii., 1904.
R.MAGNUS. Pfliiger's Archiv, cii., 1904; ciii., 1904; cxi., 1906; cxv., 1906.
Ergebnisse der Physiologie, vii., 1908.
V. B. CANNON. American Journal of Physiology, i. and vi., 1898-1901-1902.
Annals of Surgery, 1898-1906.
J. YANASE. Pfliiger's Archiv, cxvii., 1907 ; cxix., 1907.
A. SCHUPBACH. Zeitschrift f. Biologie, li. , 1908.
Auto-digestion : —
J. HUNTER. Philosophical Transactions, 1772.
SPALLANZANI. Dissertazioni sulla digestione, Modena, 1780.
BERNARD. Lesons de phys. exp., 1856.
INZANI and LUSSANA. Annali univ. di med., 1862.
SCHIFF. Le9ons sur la physiol. de la digestion, 1868.
PAVY. Guy's Hospital Reports, 1856-68. Philosophical Transactions, 1869.
GAGLIO. Lo Sperimentale, 1884.
GASPARDI and VIOLA. Atti dell' Accad. med. di Perugia, 1890.
CONTEJEAN. Arch, de physiologic, 1894.
FERMI. Riforma medica, 1895.
MATTHES. Virchow's Archiv, 1895.
P. OTTE. Travaux du lab. de L. Fredericq, 1896.
WEINLAND. Zeitschrift fiir Biologie, xliv., 1902.
262 PHYSIOLOGY CHAP, iv
Recent English Literature : —
W. M. BAYLISS and E. H. STARLING. The Movements and the Innervation of the
Large Intestine. Journ. of Physiol., 1900-1, xxvi. 107-113.
W. M. BAYLISS and E. H. STARLING. The Movements and the Innervation of the
Small Intestine. Journ. of Physiol., 1900-1, xxvi. 127-138.
B. MOORE and T. J. BERGIN. On the Chemical Reaction of the Intestinal Contents
to Various Indicators, and on the Nature of the Contents escaping from a
Fistula immediately above the Ileo-caecal Valve. Amer. Journ. of Physiol.,
1900, iii. 316-325.
B. MOORE and W. H. PARKER. On the Functions of the Bile as a Solvent. Proc.
Roy. Soc. of London, 1901, Ixviii. 64.
W. B. CANNON. The Movements of the Intestines studied by means of the
Rontgen-rays. Amer. Journ. of Physiol., 1902, vi. 251-277.
J. LEWKOWITSCH and J. J. R. MACLEOD. The Hydrolysis of Fats in vitro by means
of Steapsin. Proc. Roy. Soc. London, 1903, Ixxii. 31.
S. W. COLE. Contributions to our Knowledge of the Action of Enzymes, Part II.
Journ. of Physiol., 1904, xxx. 281-289.
H. M. VERNON. The Peptone-splitting Ferments of the Pancreas and Intestine.
Journ. of Physiol., 1904, xxx. 330-369.
E. BARCLAY - SMITH and T. R. ELLIOTT. Antiperistalsis and other Muscular
Activities of the Colon. Journ. of Physiol., 1904, xxxi. 272-304.
T. R. ELLIOTT. On the Innervation of the Ileo-Colic Sphincter. Journ. of Physiol.,
1904, xxxi. 157-168.
W. B. CANNON. The Passage of Different Food-Stuffs from the Stomach and
through the Small Intestine. Amer. Journ. of Physiol., 1904, xii. 387-418.
S. G. HEDIN. Observations on the Action of Trypsin. Journ. of Physiol., 1905,
xxxii. 468-485.
J. N. LANGLEY and R. MAGNUS. Some Observations of the Movements of the
Intestine before and after Degenerative Section of the Mesenteric Nerves.
Journ. of Physiol., 1905-6, xxxiii. 34.
A. W. HEWLETT. The Action of the Bile upon the Ester-Splitting Action of
Pancreatic Juice. Johns Hopkins Hospital Bullet., 1905, xvi. 166.
S. G. HEDIN. Further Observations on the Time-Relations in the Action of Trypsin.
Journ. of Physiol., 1906, xxxiv. 370.
PH. SHAFFER. Metabolism Experiments upon a Woman with a Permanent Biliary
Fistula. Amer. Journ. of Physiol., 1906-7, ii. 71, and 1908, iv. 45.
A. S. LOEVENHART and C. G. SOUDER. The Effect of Bile upon the Hydrolysis of
Esters by Pancreatic Juice. Journ. of Biol. Chem., 1906-7, ii. 415.
R. H. A. PLIMMER. On the Presence of Lactose in the Intestines of Animals and
on the Adaptation of the Intestine to Lactose. Journ. of Physiol., 1906-7,
xxxv. 20.
A. E. BOYCOTT and G. C. C. DAMANT. A Note on the Quantities of Marsh-Gas,
Hydrogen, and Carbon Dioxide produced in the Alimentary Canal of Goats.
Journ. of Physiol., 1907-8, xxxvi. 283.
C. A. HERTER. The Occurrence of Skatol in Human Intestine. Journ. of Biol.
Chem., 1908, iv. 101.
A. J. KENDALL. Some Observations on the Study of the Intestinal Bacteria.
Journ. of Biol. Chem., 1909, vi. 499.
G. BARGER and G. S. WALPOLE. Isolation of the Pressor Principles of Putrid
Meat. Journ. of Physiol., 1907, xxxviii. 343.
H. H. DALE and W. E. DIXON. The Action of Pressor Amines produced by
Putrefaction. Journ. of Physiol., 1909-10, xxxix. 25.
G. BARGER and H. H. DALE. Chemical Structure and Sympathomimetic Action
of Amines. Journ. of Physiol. , 1910-11, xli. 19.
H. H. DALE and P. P. LAIDLAW. The Physiological Action of /3-iminazolylethyl-
amine. Journ. of Physiol., 1910-11, xli. 318.
G. BARGER and H. H. DALE. |8-iminazolylethylamine a Depressor Constituent
of Intestinal Mucosa. Journ. of Physiol., 1910-11, xli. 499.
CHAPTEE V
INTERNAL RESTITUTIVE SECEETIONS
CONTENTS.— 1. Gastric absorption. 2. Intestinal absorption. 3. Fate of the
different groups of food-stuffs after absorption. 4. Importance of living epithelium
to absorption of crystalloid substances (salts and sugars). 5. Absorption of
neutral fats in form of soaps ; synthetic regeneration by epithelium of intestine.
6. Absorption of proteins, proteoses, and peptone ; synthetic regeneration.
7. Mechanism of internal secretion of absorbed and regenerated compensation-
products. 8. Formation of glycogen (amylogenesis) and glucose (glycogenesis) by
hepatic cells. 9. Hepatic glycogenesis an 'internal secretion ; regulation by
nervous system. 10. Derivation of hepatic and muscular glycogen from carbo-
hydrates of food. 11. Derivation of glycogen from decomposition of proteins and
fats (diabetes mellitus from pathological causes, experimental diabetes from phloridzin
and removal of pancreas). 12. Accumulation of alimentary fat ; adipogenesis.
13. Accumulation and consumption of alimentary protein. 14. Protective function
of intestinal epithelium and liver. Bibliography.
IN proportion as the food-stuffs are altered by digestion in
their passage through the alimentary canal, and are transformed
from insoluble into soluble substances, from such as are not
diffusible into such as are readily diffused, they are absorbed by
the epithelium of the gastro-intestinal mucous membrane, and
are converted into Chyle, which is then poured out by internal
secretion into the lymph sinuses of the mucosa. Chyle there-
fore denotes, not the total product of digestion, but rather the
sum of such natural or digested food-stuffs as are discharged
into the lymph torrent by internal secretion, after their partial
regeneration into the constituents of lymph and blood — which is
the synthetic or anabolic function of the living cells of the
absorbing mucous surface. Hence the concept of " chyle " is
purely theoretical. The milky fluid which can be collected
during digestion from a fistula of the thoracic duct and from the
larger cliyliferae or lacteal vessels is not really the whole of the
chyle. It does not contain all the substances absorbed and
transformed by the gastro-intestinal mucous membrane, in their
relative proportions, since a large part of these substances are taken
up by the blood capillaries of the mucous coat (particularly in the
villi of the small intestine) and carried to the liver by the portal
system, while another considerable part are absorbed by the solitary
263
264 PHYSIOLOGY CHAP.
and agminated follicles and by the lymph glands interposed along
the lacteals. The chyle poured out (with the lymph) into the
left subclavian vein contains a comparatively small proportion of
the total of the food-stuffs elaborated by the secreting and absorbing
cells of the gastro-intestinal mucous membrane, and destined to
compensate the tissues for their losses.
The title Internal Restitutive Secretions given to this chapter
comprises the study of all those complex processes by which
the individual groups of food-stuffs (which may or may not
have suffered the chemical metamorphoses of digestion discussed
in the two preceding chapters) are absorbed, partially regenerated,
secreted into the lymph spaces of the mucosa, carried away by the
lacteals and venous portal system, stored up in the various organs,
tissues, and cells as reserve materials, and finally poured out or
secreted into the blood, to compensate for the losses caused by
assimilation and the functional work of the tissues.
I. The Mucous Membrane of the entire tract of the alimentary
canal, from mouth to anus, forms, on account of the epithelium
which covers it, a single, extended, absorbing surface. But the
mouth, pharynx, and oesophagus, owing to the thickness of the
stratified epithelium, and to the fact that the food does not remain
long enough in them to undergo any important chemical digestive
modifications, play no perceptible part in absorption, although
certain intoxications prove that they are capable of it.
On the other hand, it is well known that the stomach does
play an active part in absorption. The simplest demonstration
of the fact is the rapidity with which certain poisons take effect,
particularly after the introduction of toxic substances in alcoholic
solution. Another obvious proof of absorption in the stomach is
seen in sections from animals killed during digestion, in which
the lymphatics of the stomach are found to be congested.
Von Mering (1893) published results of his accurate observa-
tions on the absorptive functions of the gastric mucous membrane,
which are important from both a hygienic and a clinical stand-
point. His method consisted in establishing a duodenal fistula on
dogs, and then introducing into the stomach a given amount of
fluids or watery solutions of various foods, after which the outflow
from the fistula was collected, measured, and analysed at con-
secutive intervals.
If the animals were allowed to drink plain water freely, it
spurted in a short time from the fistula in jets that recurred 2-6
times per minute ; 2-15 c.c. of water were excreted at each jet.
Von Mering ascertained by over 100 tests that the quantity of
fluid escaping from the fistula was approximately equal to that
introduced, and might even be larger, owing perhaps to the
saliva that became mixed with it during deglutition. He con-
cluded that water was not absorbed by the stomach in any •
v INTERNAL EESTITUTIVE SECRETIONS 265
perceptible amount. Against this, however, we must set the
fact that evacuation of the stomach does not occur as rapidly
when the duodenal fistula is obstructed, on which the fluid is
prevented from escaping to the outside, and is forced into the
intestine. This is due, according to von Mering, to the fact that
the fluid on filling the small intestine reflexly delays the flow
from the stomach, and increases the tone of the pyloric valve.
Under these conditions (which correspond to the normal) it is
probable that absorption of water by the gastric walls is con-
siderable.
When, instead of plain water, salt solution is introduced into
the dog's stomach by the duodenal fistula, the -liquid that flows
out of the fistula 'con tains much less salt and much more water.
The stomach must, therefore, absorb the salt and excrete the
water. After injecting, e.g., 30 grms. of sodium chloride dissolved
in 400 c.c. water into the stomach, 6'5 grms. of salt were absorbed,
and 787 c.c. of fluid escaped from the fistula. The same fact
appears on injecting a solution of glucose into the stomach : part of
the sugar is absorbed, and the volume of fluid escaping from the
fistula is much increased.
When solutions of proteose and peptone are injected into the
stomach of dogs with a duodenal fistula, the quantity absorbed
increases with the concentration of the solutions. In this case,
moreover, that part of the water which forms the solvent is
absorbed as well as part of the dissolved substances. According
to von Mering, the gastric mucous membrane can, under the
most favourable conditions, absorb 60 per cent peptone, while it
can only absorb 20 per cent sugar. Concentration of peptone
solution promotes absorption of water, but the contrary takes
place for sugar.
Considerable influence is exerted upon gastric absorption by
substances that excite the epithelium of the stomach, e.g. alcoholic
beverages, and the usual condiments and spices.
Alcohol is entirely absorbed, and greatly assists absorption of
the substances dissolved in it. Salt, in the amount that is
agreeable to the palate and is commonly used as a condiment
(about 2 per cent), also favours absorption, as do also mustard,
pepper, nutmeg, ginger, etc. These condiments accordingly not
only excite gastric secretion (as is commonly stated), but also
facilitate absorption of foods which are naturally soluble or have
become soluble by digestion in the stomach — either by exciting
the absorbing epithelial cells, or by provoking active hyperaemia
and improved circulation in the blood and lymph capillaries of
the mucous membrane.
II. The tract best adapted to digestion is undoubtedly the
Mucous Membrane of the Gut, especially that of the small intestine,
more particularly of the duodenum and jejunum, where there
266
PHYSIOLOGY
CHAP.
are large valvulae conniventes and the villi are long and very
numerous. The visible surface of measurement of the small
Fio. 87.— Cross -section of a villas of cat's intestine. Highly magnified. (E. A. Schiifer.)
e, columnar epithelium ; g, goblet-cell with mucus partly exuded ; I, lymph-corpuscles between
the epithelium cells ; b, basement-membrane ; c, blood corpuscles ; m, section of plain muscular
fibres ; d, central lacteal.
intestine extends in the adult to some half a square metre. But
the many folds of the valvulae con-
niventes, and extensive inflexions and
projections of the mucous coat of the
villi, increase the true surface of this
part of the mucous membrane to
about 10 square metres. The chyme
is distributed over this vast absorbing
surface, so that absorption — the main
function of the epithelium that clothes
the villi as well as the solitary and
agminated glands scattered over the
small intestine — is greatly facilitated.
The villi, as the chief organs of
absorption, claim special attention.
They vary in length from Q'5-0'7 mm.,
are larger and more numerous in the
duodenum and jejunum, and diminish
in size and number in the ileum.
to Krause, each square
millimetre of the jejunum contains
10-18, of the ileum 8-14 On the
basis of this calculation the total
number of villi in the whole of the
small intestine may be taken as four
to five millions, and each square centimetre of the apparent surface
of the intestine gains about twenty-three times in area from the
Fio. 88. — Injected lacteal vessels in two
villi of human intestine. (Teichmann.)
100 diameters. The lacteals are filled A r>f>nrrl 1 n cr
with white substance ; the blood- „ u ^ &
vessels with dark, a, b, lacteals, single
in one villus, double in the other ;
c, horizontal lacteals, communicating
with those of the villi; d, blood-
vessels which consist of small arteries
and veins with capillary network
between.
INTERNAL RESTITUTIVE SECEETIONS
267
protrusion of the villi. As shown in Fig. 87, they consist of a
special epithelium which encloses a lymphoid tissue : in the centre
of this is a lacteal, the wall of which consists of simple epithelioid
cells with wavy outlines, which in all probability have little stomata
Tad
FIG.
-Cross-section through villus: A, of dog ; B, of rabbit. (Heidenhain.) C, central lacteal
T.od, adenoid tissue ; E, epithelium with striated cuticle.
or spaces at the junction of the cement substance. The central
lymphatic (which sometimes consists of two vessels joined at the
end by a loop, as shown in Fig. 88) communicates with the sub-
jacent intermuscular lymph plexus. The adenoid tissue of the
villi is generally more developed in carnivora than in herbivora,
in which, on the other hand, the central lymphatic is much wider
FIG. 90.— Magnified blood-vessels of intestinal villi. (Sharpey.) From specimen injected by
Lieberkiihn. Each villus shows a small artery and vein with capillary network between.
(Fig. 89). The adenoid tissue of the villi is also traversed by a
vascular loop consisting of small arteries and veins, united by a
capillary network (Fig. 90). The retiform adenoid cells are inter-
mixed with muscular tissue which is a prolongation of the
muscularis mucosae (Briicke), and the meshes or lacunae which
they form contain numerous lymphocytes, filled with granules,
which stain black with osmic acid, but do not consist of fat, since
268
PHYSIOLOGY
CHAP.
they are insoluble in ether (Heidenhain). Lastly, according to
llainon y Cajal, the lymphoid tissue of the villi presents a very
fine plexus of nerves, the peripheral termination of the coarser
plexus of Meissner which is situated in the submucous layer of the
intestine (Fig. 91).
The columnar epithelium with a striated border which clothes
the villi (see Fig. 43, p. 124) is apparently identical with that of
the crypts of Lieberkiihn, but the latter stains more intensely with
various pigments, and its
border is much less plainly
striated. Moreover, the
nuclei of the latter often
exhibit mitotic division,
while karyokinetic figures
are never seen in the
epithelial cells of the villi.
These differences probably
indicate (as' maintained
by A. D. Waller) that the
normal function of the
epithelium in the crypts
is the external secretion
of succus entericus, while
the epithelium of the villi
is an organ of absorption
and internal secretion of
the absorbed substance.
This removes the diffi-
culty which some physio-
logists find in admitting
FioOl.-Nerve endings from small intestine of guinea-pig fcWO opposite and
Potassium chromate and silver nitrate method. (Cajal.) r. . „ ,
a, 6, c, d, small nerve-cells belonging to the inter- tanCOUS functions IOr the
glandular plexus of the mucous membrane ; c, /, corre- _OTV1_ .-..-.llc, tn-nmam^ninnm
spending cells belonging to nerve plexus of villi; M, S<*m.i US, iranSUaCtlWf
Fnerrusficu?arisemucgosfe.to Meissner's plexus> distributed and alsorption. We shall
find direct evidence for
this theory when we examine the absorption. of fats in detail.
Not only from the great extension of the absorbing surface,
but also from the various chemical digestive processes which the
chyme undergoes in the small intestine (owing chiefly to the
action of the various enzymes of the secretions poured into it),
absorption along the whole of this tract is more active than in the
stomach. Of this the case of duodenal fistula described by Busch
gives plain evidence. Although the patient was abundantly fed
by the mouth, she suffered continually from hunger, and in a few
weeks her weight went down so much that she was threatened
with death from marasmus, which was only averted on feeding her
through the lower end of the fistula. In the cases of fistula at the
v INTERNAL RESTITUTIVE SECEETIONS 269
end of the ileuni described by Braun and Ewald, on the contrary,
the body-weight was tolerably well maintained on an abundant
diet per os, notwithstanding the considerable loss of nutritive
substances through the fistula.
The maximal degree of absorption of the food-stuffs from
the chyme is effected principally in the duodenum (below the
orifices of Wirsung's duct and the common bile duct) and the
jejunum. Ruggi's case of extensive resection of the ileum referred
to in the last chapter (iv. § 5), in which the faeces did not contain
an abnormal excess of proteins, fats, and carbohydrates, is a direct
proof that, owing to physiological adaptation, nearly the whole of
the intestinal absorption can be performed in the upper part of
the small intestine.
Normally, therefore, no absorption of food-stuffs worth noting
takes place in the large intestine. The absence of villi (see Fig.
42, p. 123) and of valvulae conniventes, and the superabundance of
mucin-secreting crypts, support this conclusion. A physiological
argument for the insignificant absorption of food -stuffs which
takes place under normal conditions in the large intestine, is
shown by the fact that in no -cases of fistula of this part of the
gut, as described for man, was any diminution of weight observed
in the individuals affected (Czerny, Marckwald). In dogs, on the
contrary, according to Albertoni, nutritive absorption is not com-
pleted in the small intestine, but continues in the large bowel.
These animals, in fact, become emaciated with a fistula of the
caecum. Har ley's recent researches confirm these observations,
and show that dogs with fistula of the large bowel absorb fats and
carbohydrates normally, but proteins only imperfectly.
Hardly anything but water is normally absorbed in the large
bowel of man. It is, in fact, in this part of the gut that the
intestinal contents assume the pasty consistency proper to faecal
matter, and the mucin secreted by the crypts of the large intestine
(supra) lubricates the surface of the faeces, and facilitates their
expulsion.
Later on we shall see how under abnormal conditions of
alimentation per rectum the large bowel is capable of absorbing
not only diffusible substances such as alcohol, salts and glucose,
but also colloidal substances, including protein.
III. Before we attack the study of the complex mechanism of
intestinal absorption, it will be advisable to obtain some idea of
the paths which the food-stuffs take after absorption, this question
being simpler and easier of solution, so that it leads up to the other.
From the time of Bartholin, who completed the discoveries of
Aselli, Pecquet, and Rudbeck on the so-called Vasa Lactea, until a
few years ago, there was a tendency to assume that the principal
stream of food-stuffs from the intestine to the blood was repre-
sented by the chyle flowing through the thoracic duct. The work
270 PHYSIOLOGY CHAP.
done in Ludwig's laboratory by his pupils Eohrig (1874), Zawilski
(1876), von Mering (1877), Schmidt-Miilheim (1877), and con-
firmed by I. Munk and Rosenstein (1890), for man in a case of
lymphatic fistula, corrected this erroneous assumption, and showed
by a great number of observations that it is only the fats (and
again only a part of these) which pass by way of the thoracic duct,
while all the other foods absorbed travel, for the most part at least,
by the blood capillaries of the villi, and pass directly to the liver
by the venous portal system.
On introducing a cannula into the thoracic duct of a dog near
its opening into the left subclavian vein, it is seen that the flow
from the cannula in the time unit is not sensibly augmented
during the period of digestion and absorption ; but the lymph,
which is semi-transparent previous to digestion, turns into chyle,
i.e. becomes opaque and milky, during digestion, particularly after
a meal rich in fatty substances. In fact, comparative analysis of
the chemical composition of the lymph and chyle from the thoracic
duct shows that the sole difference between the two fluids lies in
the preponderance of fat in the chyle, which varies in character
according to the nature and amount of the fats ingested. Most of
it is present as emulsified neutral fats, in the form of the finest
droplets visible under the microscope, which dissolve in ether,
and stain black with osmic acid. A small part (about -^) &
present in the form of saponified fatty acids. After a meal rich in
fatty substances the chyle collected from man may contain 4'7 per
cent fat (I. Munk), and that from the dog 14'6 per cent (Zawilski) ;
while the lymph that flows from the fistula in the fasting state
contains only 0'06-0'26 per cent.
This naturally leads to the question whether the whole of the
alimentary fat absorbed by the gastro-intestinal mucous membrane
passes by the thoracic duct to reach the blood stream, or whether
part of it may pass along the portal system or by other paths.
On giving a measured quantity of fat to a dog with fistula of the
thoracic duct, and subtracting the small amount of fat which
leaves by the faeces, we obtain approximately the quantity of fat
absorbed, which may be compared with the total amount that
escapes by the fistula during the whole time in which the lymph
preserves the milky appearance of chyle. On estimating this
quantity, it is found to be about 40-50 per cent of the total fat
absorbed. There is thus a deficit of 50-60 parts of the fat, which
must pass into the blood, not by the thoracic duct, but by some
other way. This fat might conceivably pass by the paths that feed
the portal system, since some authors have found that the serum
separated from the portal blood was also milky during digestion.
According to Foster, however, this argument is fallacious, because
during the digestion of a meal rich in fats the whole of the blood,
including that of the carotid, contains much fat, and the serum of the
v INTERNAL RESTITUTIVE SECRETIONS 271
latter is more milky than that of the portal vein, showing it to be
fat absorbed from the lacteals and not from the blood capillaries of
the intestinal villi. This is proved by the fact that during the flow
of chyle from the fistula of the thoracic duct the portal blood
contains a very small amount of fat. The deficit of absorbed fat
can, therefore, only be explained, according to Foster, on the
assumption that, as it passes through the lymph glands of the
mesentery, part of it escapes from the chyle and the blood torrent
by unknown ways, and by a process of which we have as yet no
conception.
Foster's view was opposed as long ago as 1901 by Munk and
Friedenthal, and in 1907 by D'Errico, who more particularly con-
tested the data on which Foster founded his theory. D'Errico
calculated the fat content of the blood collected from the portal
and jugular veins, and proved that under normal conditions, after
a meal rich in fats, the former contained more fat than the latter
(0412-0-385 per cent in the portal blood, 0'280-0'212 per cent in the
blood of the jugular). This difference was not less in the samples
of blood collected after deflecting the mouth of the thoracic duct to
the exterior (0412-0-315 per cent of fat in the portal, 0'205-0'208
per cent in the jugular).
If this larger fat content of the portal blood is to be ascribed
to the fat absorbed by way of the blood-vessels, we must conclude
that absorption by this path is considerable, seeing the large
amount of blood that circulates in the portal system during the
period of digestion. It must, however, be remembered that the
work so far carried out on the fat content of the blood is unreliable
because, as Kumagawa and Suto showed (even if they are taken
comparatively), the methods employed may lead to grave errors
which make any interpretation of the results questionable. It is
advisable to regard the subject of the paths of fat absorption as an
open question, which has not been decided by Foster's theory.
While the question whether part of the fat is absorbed by the
capillaries of the villi, and passes by the venous paths of the portal
system, is thus under discussion, it is indisputable that the sugar
introduced with the food, as well as that formed during the
digestion of carbohydrates, under conditions of normal alimenta-
tion traverses the portal system exclusively, and is carried by it to
the liver. Von Mering's accurate researches (1877) show that the
percentage sugar content of the chyle collected from the thoracic
duct is not perceptibly greater than that of the lymph collected
before a meal, and that of the arterial blood, which never exceeds
0'06-0'16 per cent. On the other hand, on comparing the percentage
amount of sugar from the blood of the portal vein with that of the
hepatic veins, it is found that while the difference is negligible
in the fasting state, it is increased during digestion in the former
(up to 04 per cent), and not in the latter. This is no great increment,
272 PHYSIOLOGY CHAP.
and might fall within the limits of experimental error ; but if we
take into account the enormous quantity of blood that circulates
in the portal system during the whole period of digestion, we
cannot doubt that sugar can be absorbed by the capillaries of the
villi, however insignificant the amount present in 100 c.c. of portal
blood may be.
It is only when the amount of sugar introduced into the
intestine is abnormally great that part of it is absorbed from the
lymphatics, and produces an increase in the sugar of the chyle
escaping by the fistula (Ginsberg, 1889). But in view of the slow
rate at which the chyle flows along the thoracic duct, it must be
remembered that even in this case of excessive dosage with sugar,
the quantity that traverses the lacteals is minute in comparison
with that absorbed by the blood capillaries and carried to the
liver. In the girl with a lymphatic fistula described by I. Munk
and Rosenstein, it was noted that at most one-half per cent of the
absorbed sugar passed through the lacteals. Since in this case
there was excessive absorption of water by the lacteals, it is
probable that the current of water carried off a part of the sugar
dissolved in it. Since the increased sugar content of the blood
during digestion can only be detected in the portal vein and not
in the hepatic veins, it follows that the sugar must be fixed and
stored up in the cells of the hepatic parenchyma. We shall see
the great importance of this fact in discussing the metabolism of
the liver.
The experimental data which are to hand in regard to the
course of the proteins after absorption are less definite. Schniidt-
Miilheim, with Ludwig, found that ligation of the thoracic duct
did not hinder protein absorption. More precise observations
were made by I. Munk and Rosenstein (1890) in the case of the
girl of eighteen with a lymphatic fistula. After a copious flesh
meal, the effusion from the fistula showed no perceptible increase
either in percentage of proteins or in absolute quantity escaping
from the fistula during the twelve hours subsequent to the meal.
From this they concluded' that no amount of absorbed protein
worth noting passes by the lacteals ; it must therefore travel by
the blood capillaries of the mucous membrane of the intestine.
Wurtz, however, prior to Munk, had observed that the chyle of
oxen before rumination contains only 3'97 per cent protein, while
after rumination the protein content was raised to 5'96 per cent.
Possibly, as Foster rightly pointed out, all proteins do not take
the same path, and are not absorbed under identical conditions by
all animals. If in herbivora, where the diet contains little fat, the
whole of the carbohydrates and proteins were absorbed by the
blood-vessels of the intestinal mucous membrane, little would be
left to pass by the lacteals. The structure of the villi shows that
the central lacteal of guinea-pigs and rabbits is larger than in
INTERNAL RESTITUTIVE SECRETIONS
273
dogs, where, on the other hand, there is more adenoid tissue (see
Fig. 89). It is difficult to reconcile this fact with the theory
that the central lacteal serves exclusively for absorption of fatty
substances.
I. Munk, who upholds this doctrine, himself cites in his Text-
book, in addition to the data he obtained from man, the results of
the comparative analyses of lymph and chyle made by C. Schmidt
and Fr. Simon and Rees on various animals, which appear to us to
speak in favour of a less exclusive theory. To facilitate com-
parison we have arranged these data in one table : —
Man.
Horse.
Ass.
Cow.
Dog.
100 parts
contain
Lymph.
Chyle.
Lymph.
Chyle.
Lymph.
Chyle.
Lymph.
Chyle.
Water .
95-2
92-2
95-8
92-8
96-5
90-2
96-4
91-2
Solids .
4-8
8-8
4-2
7-2
3-5
9-8
3-6
8'8
Fibrin .
o-i
1-0
o-i
o-i
o-i
0-4
o-i
1-0
Proteins
3-5
3-2
2-9
4-0
27
3'5
2-8
27
Fats .
Trace
3-3
Trace
1-5
Trace
3'6
Trace
4-9
Extractives
0-3
0-4
0-1
0-8
o-i
1-6
o-i
0-3
Salts .
0-9
0-8
1-1
0-8
0-6
07
0-6
0-8
IV. The history of physiology has not seldom shown that new
achievements in the field of physical science give rise to the
illusion that a part of the mystery which veils the subtle mechanism
of the vital processes has been cleared away. After Dutrochet's
discovery of diffusion through permeable membranes of substances
in solution, it was held by many, without direct experimental
tests, that Food Absorption in the Intestine was a phenomenon of
the same order, easily explicable on the laws of osmosis, and that
the sole physiological object of the chemical processes of digestion
was to render the ingested foods diffusible through the animal
membrane formed by the epithelial layer of the intestine.
But when this doctrine came to be experimentally tested a
number of facts were brought to light which showed that intestinal
absorption is no such simple phenomenon, and th'at the living
walls of the intestine are not comparable with an inert porous
membrane.
As early as 1869, Voit and Bauer observed the absorption of
blood serum injected into a loop of intestine, a phenomenon that
cannot be explained by a simple process of diffusion : few, however,
realised the importance of this fact, and the absorption of fluids
from the intestine continued to be regarded as an effect of osmosis.
Hoppe-Seyler (1881) criticised this theory, and held that the
passage of the intestinal fluids into the circulation was not a
simple effect of the chemical differences between fluids separated
VOL. II T
274 PHYSIOLOGY CHAP.
by a permeable membrane, but was rather due to the specific
activity of the living epithelium that clothes the intestine. This
idea was supported by a series of experiments carried out in
Heidenhain's laboratory, and published by Leubuscher in 1885.
Even after this, however, there remained no little uncertainty as
to the point at which the laws of diffusion intervened and
favoured the phenomenon of absorption. .
Albertoni in 1891 pointed out that the absorption of sugars
took place equally, whether the specific gravity of the solution was
greater or less than that of the blood. In 1892 his first results
were confirmed by new experiments and brought out an important
fact, viz. that absorption of sugars (glucose, lactose, maltose)
which had been freely administered was most active in the
first hour, and much less in the succeeding hours relatively to the
quantity that remained in the alimentary canal. The reason of
this phenomenon is unknown. It seems not to depend on satura-
tion of the body by glucose, as Albertoni at first assumed, because
he afterwards found that the osmotic pressure of the blood alters
very little during absorption of sugar. Since his experiments
showed that the colloidal content of the blood increases consider-
ably after the first hour of absorption, he thought this fact was
probably in causal relation with its subsequent diminution.
In order to solve the problem of absorption, it was necessary to
attack it again in the light of more advanced physical methods,
particularly in reference to the absorption of those easily diffusible
substances which were classed together by Graham under the name
of crystalloids. Among the alimentary substances that come
under this category we find especially the Salts and the Sugars,
sodium chloride and glucose in particular.
Heidenhain (1894) was the first who undertook an exhaustive
criticism of the Theory of Intestinal Absorption. He found that
solutions of sodium chloride with an osmotic pressure greater than,
or equal to, blood, were, when injected into an isolated loop of
intestine in a fasting dog, absorbed indifferently, although in the
first case (according to the laws of osmosis) hardly any water should
have passed from the intestine to the blood, and in the second no
absorption at all should have taken place. He concluded that the
absorption could only be explained as the effect of specific forces
inherent in the living cells of the wall of the intestine. In his
opinion this conclusion was confirmed by the fact that when the
intestinal epithelia were functionally injured by a moderate
poisoning with sodium fluoride without any perceptible cytological
change, the absorption of the foregoing solutions was modified so as
to be in complete agreement with the laws of osmosis.
These results of Heidenhain were confirmed by Hamburger
(1895-96). He, too, found that solutions of sodium chloride, sodium
nitrate, or sugar, with a greater or less osmotic pressure than the
v INTERNAL RESTITUTIVE SECRETIONS 275
blood-serum of the animal experimented on, became in the course
of absorption isotonic with the latter, and were all eventually
absorbed. But since he found that the same phenomena of absorp-
tion of solutions which were isotonic, and also of such as were
hypertonic, with the serum, could be obtained from animals
killed some hours previous to experiment, he denied the importance
which Heidenhaiu allotted to the living cells, and invoked the
imbibition of the colloidal substances of which the epithelia consist
as a possible explanation of the facts which Were opposed to the
laws of diffusion.
Heidenhain at once replied that it is not possible to establish
a comparison between the phenomena that can be observed on
living animals with circulating fluids that are rapidly renewed,
and those observed on dead animals in which the fluids con-
tained in the depth of the intestinal walls stagnate. It is obvious
that even if the phenomena are apparently similar in the two
cases, they will not bear the same interpretation. It must also
be remembered that in the living animal there is simultaneously
with the phenomenon of intestinal absorption a secretion of succus
entericus, i.e. a current opposed to that of absorption, which is
absent in the dead animal.
0. Cohnheim (1897), in Klihne's laboratory, repeated Ham-
burger's experiments on the absorption phenomena in living and in
dead dogs, under proper experimental conditions, and his results
confirmed and extended the theory of Heidenhain. On circulating
a continuous current of 0'9 4 per cent salt solution heated to 40° C.
through the blood-vessels of the dead animal, and introducing a
solution of glucose into a loop of intestine tied at the ends, he saw
that a double current was set up, so that part of the sodium
chloride passed into the intestine, and part of the sugar into the
circulating fluid. Each of the dissolved substances diffused inde-
pendent of the other, according to their respective degree of diffusi-
bility. The salt being three times as diffusible as the sugar,
passed much more rapidly from the capillaries into the intestine
than the sugar from the intestine to the capillaries. Under these
conditions, therefore, the mucous membrane behaves like any inert
membrane, and the double current which passes through it
conforms perfectly to the laws of diffusion and osmosis. There
is never any diminution of fluid in the loop ; with both hypotonic
and hypertonic solutions, there is always an undoubted increase of
the fluid in the intestine. The possibility of absorption, as it takes
place in the small intestine in living animals, is therefore bound
up with the integrity and functional capacity of the intestinal
epithelium. According to the results obtained by Cohnheim, the
epithelium of the gut is capable of absorbing, inasmuch as it is
the seat of a specific force which favours the passage of the
dissolved substances from the intestine into the depths of the villi,
276 PHYSIOLOGY CHAP.
and impedes their passage in the reverse direction. This capacity
of the epithelium for letting certain solutions through in one
direction only is met with in many other cells, which, so long as they
are alive, possess a wall that is impenetrable to certain substances,
and lose this property after death, on which an exchange takes
place between the materials they contain and those of the environ-
ment. Cohnheim reminds us in this connection of the erythrocytes
and the muscles, which in many animals are devoid of sodium and
rich in potassium, although they may live in a medium rich in
soda and poor in potash. Plant cells, again, are colourless so long
as they are alive, although surrounded by a coloured juice, which
only penetrates their protoplasm when life is extinct. To the
same order belongs the fact discussed at length at the end of
the last chapter, viz. that the cells which form the intestinal wall
never, wThile living, allow themselves to be penetrated by the
digestive enzymes, so that auto-digestion takes place only after
death.
In affirming, on the basis of well-established experimental
data, that intestinal absorption is not regulated by the physical
laws of diffusion, we do not mean that this process is of no
importance, and plays no part in absorption. The Living cell (as
we saw in the first three chapters of VoL I.) is the seat of a highly
complex metabolism, which consists of various chemical and
physical processes adapted to specific functional tasks. It would
be absurd to suppose that diffusion and osmosis do not figure
among the physical processes employed by the cell to accomplish
absorption. It would then be impossible to understand why non-
diffusible become converted into diffusible substances during
digestion. But the process of diffusion utilised 'in absorption is
adapted and modified to the service of a special function, so
that it differs essentially in its results from the diffusion which
takes place through a non-living porous septum. Foster gives a
suggestive interpretation of this difference : " The canals or spaces
are constant in a non-living septum ; but a film of a living cell
may be conceived of as a diffusion septum the pores of which are
continually varying, and, moreover, as closing up or opening out at
the touch of this or that substance ; hence the passage of material
through the pores of a living cell takes place according to laws
quite different from those of ordinary diffusion."
The capacity for physiological selection which Spiro (1897)
attributes to living cells in general must be understood in the
same sense, and is entirely different from the physical selection
accomplished by dead tissues.
This physiological theory of intestinal absorption is sub-
stantially confirmed by the later work of Hober (1898-1903) and
Cohnheim (1898-99).
The former made a comparison in dogs between the absorption
v INTERNAL RESTITUTIVE SECRETIONS 277
of sodium chloride solution in a loop of the gut, and solutions of
sodium sulphate and a number of other inorganic neutral salts.
Among the most important results of his work may be noted the
fact that isotonic solutions of the various salts are absorbed at
different rates by the intestinal wall, independent of the molecular
weight of their ions, and the different degree of their electrolytic
dissociation. This shows that the wall of the intestine does not
behave like a more or less permeable homogeneous membrane, but
like a membrane with specific properties.
0. Cohnheim's experiments are a continuation of those of
Heidenhain upon the changes effected in intestinal absorption by
the action of poisons which alter or destroy the vitality of the
intestinal epithelium. With this object he compared the absorp-
tion in a loop of intestine of sugar solutions at equal concentra-
tion, before and after the addition of various poisons (sodium
or potassium fluoride, potassium arseniate, etc.) in such small
quantities as not to injure the animal. According to the degree
of intoxication of the intestinal epithelium, he obtained a decrease
or complete cessation of absorption. He noted further that the
poisoned mucous membrane gave the same results as in the dead
animal, i.e. the intestinal wall lost its property of being traversed
in one direction only. The sugar solution introduced into the
loop was found under these conditions to contain a considerable
quantity of sodium chloride from the blood and lymph vessels.
Normal absorption is thus proved not to be the effect of any merely
physical process, since it is so profoundly altered by a few
milligrammes of a given substance. Granting this to be the
effect of poisoning, it follows that absorption must have a living,
organised substrate, since this alone is capable of intoxication.
Cohnheim justly distinguishes two factors in intestinal absorption :
the impenetrability of the wall of the gut to the circulating fluids,
and its capacity for absorbing solutions from the intestine. Both
these factors, and each independently of the other, can be altered
or suppressed by intoxication.
If the absorption of crystalloids (represented by salts, sugars,
and ammo-acids) is not governed by the laws of diffusion and
osmosis, but depends on the specific physiological activity of the
mucous membrane, and particularly of the epithelial cells which
cover it, we may assume a fortiori that the absorption of colloids
(represented by proteins, proteoses, and peptones) which provide
the essentials of nutrition, must equally be independent of these
physical laws, whether they are changed or left unchanged by the
digestive processes.
Before leaving the subject of the absorption of salts and
sugars, it must be added that they suffer no chemical change
through the metabolic activity of the epithelial cells while travers-
ing the wall of the intestine — which, as we shall see, is not the
278 PHYSIOLOGY CHAP.
case for fats and proteins. Of this there can be no doubt, either for
salts or sugars. We saw in the last chapter that all the alimentary
carbohydrates are converted by the chemical processes of digestion
into monosaccharides, i.e. into the form of simple sugars, more
particularly into glucose, before absorption. They are thus
absorbed and carried to the liver by the portal system in that form
in which they circulate normally in the blood. The disaccharides,
i.e. saccharose, maltose, and lactose (which are bimolecular
anhydrides of the monosaccharides) are not usually absorbed as
such, but are first hydrolysed, with addition of one molecule of
water, by the action of the succus entericus. It is only when
highly concentrated solutions are introduced that they are partially
absorbed unchanged, the proof of this being that when they reach
the blood they do not remain there, but are at once excreted by
the kidneys. The polysaccharides, i.e. dextrin, the starches and
gums, and cellulose (which are polymeric anhydrides of the simple
sugars) cannot be absorbed without first undergoing the amylolytic
action of the saliva and pancreatic juice. Dextrin and amygdalin
alone are sometimes held to be absorbed in small amounts, but
this fact has not been proved, and is in any case very obscure.
V. The question of the process of Fat Absorption, and the
chemical form into which the fats must be converted previous to
absorption, is more complicated.
Till recently, the theory that fat was principally absorbed in
the form of a fine emulsion of glycerides (or neutral fats), a fraction
only being absorbed as soaps (formed by the combination of the
fatty acids liberated by the lipolytic action of steapsin and the
intestinal bacteria with the alkali of the secretions of the
intestine) was uncontested. On this theory the cleavage of the
glycerides is not a digestion, indispensable to the absorption of
the fat : it merely furnishes a small amount of soluble soaps
which facilitate the emulsification of the neutral fats — these
being mainly absorbed as an emulsion of microscopic granules.
This theory was first put forward by Briicke, and was after-
wards supported by the physiological and histological observations
of several authors. But further advances in research cast grave
doubts upon its probability — at least as a general statement.
In order to remove the difficulties encountered in regard to
the mechanism by which the fat globules could penetrate into the
interior of the epithelial cells, Perewoznikoff (1876) and Will
(1879) proposed the hypothesis that the whole of the ingested
fats are split into fatty acids ; that they are absorbed in this form
or as soluble soaps by the epithelium ; and that when absorption
has taken place, they are regenerated into glycerides or neutral
fats by a synthesis performed by the anabolic activity of the
epithelial cells. These authors demonstrated that in the frog, after
feeding with pure fatty acids or soaps, with or without the addition
v INTEKNAL KESTITUTIVE SECEETIONS 279
of glycerol, and then .treating the intestinal epithelium with
osmic acid, the same microscopic results were obtained as after
feeding with neutral fats. Will observed the same thing, even
when the frog is fed with fats of such a high melting-point, that
they cannot be liquefied and emulsified in the intestine. Ewald
made the same observations on the intestinal epithelium in 1883,
after stripping off the mucous coat of the intestine, and setting it
to digest at body-temperature in a solution of soaps and glycerol.
This shows that synthesis of the fatty acids and glycerol may be
effected by the epithelial cells which survive the separation from
the body.
On the other hand, we know from countless observations,
particularly those of Cash, in Ludwig's laboratory (1881), of
I. Munk (1885), and Heidenhain (1888), that the intestinal chyme
of the dog is almost always acid from the pylorus to the ileo-caecal
valve, and that consequently the fat which it contains is not
emulsified, or at any rate only imperfectly so, and exhibits drops
of fat many times coarser than those observed under the microscope
in a true emulsion. And yet, Munk says expressly, it can be
seen in the parts of the small intestine in which the chyme is
acid, and in which the non-emulsified fat floats here and there in
large drops, that the lymphatics of the mesentery are full of
milky chyle, a proof that fat absorption is going on, even when
it is not emulsified and when the chyme has an acid reaction.
This observation proves that the fat is absorbed under another
form, perhaps in that of fatty acids or of soaps. In fact, when
soaps or fatty acids are fed to a dog, small fractions only reappear
in the faeces, if fatty acids with a low melting-point are taken.
On analysing the chyle resulting from these experiments, it is
found to contain a large quantity of neutral fats, while the
content of free fatty acids and soaps has hardly increased at all,
and is very insignificant. This fact agrees perfectly with the
theory which admits that the fats, like all other food-stuffs, are
absorbed in the form of solutions, i.e. after cleavage, and are
synthetically regenerated after penetrating the cytoplasm of the
epithelial cells.
Other more direct arguments in favour of this theory are
furnished by microscopical observations of the intestinal epithelia
iu successive phases of fat absorption. All who have occupied
themselves with this subject (Kolliker, Will, Ewald, Eimer,
Eanvier, and others) agree in admitting that certain parts of the
columnar cell and the whole of the striated border, in particular,
are always quite free of fat-drops.
The results obtained by Altmann (1889) and his pupil Krehl
(1890) are more decisive. If osmic preparations of the frog's
intestinal epithelium are studied in various stages of fat absorption,
the cytoplasm is seen to be full of granules, the size of which
280
PHYSIOLOGY
CHAP.
gradually increases (from mere dots to large spherules) in suc-
cessively longer intervals from the meal. In proportion as they
become longer the granules stain more deeply with osmic acid :
the least are round particles slightly tinged with grey, the larger
FIG. 92.—
, ,
feeding; C, rana esculenta in winter, 4th day after feeding with cream ; D, rana temporaric in
summer, 8 hours after feeding with olive oil. The fat droplets are stained more or less black
with osmic acid.
are spherules of a distinct black colour (Fig. 92). According to
Altmann's theory of the granular structure of protoplasm, the
punctiform particles, which hardly stain with the osmic acid, would
be the elementary granules that subserve the protoplasmic
function, surrounded by a kyer of fat synthetically regenerated
v INTEKNAL EESTITUT1VE SECKETIONS 281
by the anabolic action of the granules ; the black spherules of
increasing size observed later on would have nuclei composed of
the elementary granules, which are invisible because they are
surrounded by a more or less extensive layer of newly formed fat.
The credibility of this hypothesis is proved by the observations of
Altmann and Krehl on fat absorption in the mammalian intestine.
The epithelial cells, in the early stages of absorption, exhibited
not grey or black granules, but blackish rings with clear centres
(Fig. 93). This appearance can only be interpreted by assuming
that the clear centres consist of unstained elementary granules
with a layer of fat at their outermost zone, which fat reached the
cells in the form of solution, and was regenerated by the anabolic
activity of the granules. These important cytological observations
Fio. 93. — Fragments of epithelium from mammalian intestine during fat absorption. (Krehl.)
About 700 diameters. A, suckling kitten, 3 hours after artificial feeding with cream ;
13, white rat, 3 hours after feeding with cream.
seem to us to afford direct evidence for the modern theory of the
absorption of fats in the form of solutions.
Other physiological arguments in favour of this theory may be
deduced from the great importance of the pancreatic juice and the
bile in the absorption and utilisation of alimentary fat. We saw
in the last chapter that the lipolytic action is due to the pancreatic
juice and that the bile has a marked coadjuvant action upon it, as
is confirmed by the effects of intestinal acholia (see p. 220 et seq.*).
It is therefore important to consider the effects of extirpation of
the pancreas and deviation of the bile from the intestine more
closely in regard to fat absorption.
Minkowski's pupil Abelmann (1890) made a great number of
experiments on fat digestion and absorption in the animals from
which Minkowski had removed the pancreas. He found that after
complete extirpation of the pancreas in dogs, the whole of the
alimentary fats (butter, lard, olive oil) reappeared in the faeces so
that no absorption had taken place. The sole exception was the
282 PHYSIOLOGY CHAP.
emulsified fat of milk, of which 53 per cent could be absorbed.
After incomplete extirpation of the pancreas, on the contrary,
absorption of about half the ingested fat, and as much as 80 per
cent of the fat of milk could be observed.
These conclusions were, however, criticised and corrected by
Hedon and Ville (1897), who employed a more perfect method of
estimating the fats in the faeces, and further investigated the
fat content of the chyle after the complete or incomplete removal
of the pancreas. They found that even in perfectly depancreatised
dogs there is a certain deficit of eliminated as compared with
ingested fat, the missing amount being found in the chyle, which
presents a milky aspect and contains a considerable amount
of fat.
The work of both Abelmann and of these French investigators
shows that cleavage of fats goes on energetically even in the
absence of the pancreas (owing to the action of the lipolytic
enzyme of the gastric juice, the succus entericus, and the intestinal
microbes), since the neutral fat ingested is found in the faeces
principally in the form of free fatty acids, much less in the form
of neutral fats, and least of all as soaps.
The phenomenon of loss of fat by the faeces in quantities
approximately equal to the alimentary fab, after the total extir-
pation of the pancreas, was confirmed by numerous observers
(Harley, Eosenberg, Baldi, Scotti, Hess, Pfliiger, etc.). These
authors all interpreted it as being due to defective absorption
owing to absence of the pancreatic secretion in the intestine.
This explanation is contradicted by the fact that absorption of
80 per cent and more of fat can be seen when a segment of about
one-third of the pancreas is left, isolated from the abdominal cavity,
and pouring its secretion away outside the body (U. Lombroso,
Fleckseder, see p. 101).
It might logically be supposed that on partial removal of the
pancreas with deviation of the secretion to the exterior, there
would be an increase in the lipolytic and enzymic activity of the
other glands which provide for the digestion of the fats and their
subsequent absorption. This hypothesis is, however, excluded by
the results of Lombroso's experiments on the enzymic activity
of the various secretions, before and after the extirpation of the
pancreas secreting outside the intestine.
That the loss of fat by the faeces in depancreatised animals
cannot be ascribed to deficiency of the lipolytic process, appears
from the fact that on administering fatty acids or soaps instead
of neutral fats, the amount of fats eliminated by the faeces of
depancreatised dogs diminishes very little (Abelmann, Lombroso).
Is it possible that the fat present in the faeces of depancreatised
animals does not consist exclusively of non-absorbed alimentary
fat, as is generally supposed, but also to a greater or less extent of
v INTEENAL EESTITUTIVE SECEETIONS 283
the fat previously stored up in the body, which is eliminated by
intestinal excretion when the internal secretion of the pancreas is
wanting ? Certain observations of Lombroso tend to justify this
bold hypothesis.
He noted excess .of fat in the faeces of certain depancreatised
animals, when fasting or fed with plain egg-albumin. If kept on
a mixed diet, the faeces contained more fat than is supplied with
the food. A similar phenomenon has previously been recorded by
Harley, but to a less extent, so that it came within the limits of
experimental error. In some other cases Lombroso observed that
the fat present in the faeces of depancreatised dogs, while not in
excess of that introduced with the food, had a different melting-
point.
These observations (to which we shall return in speaking of
the excretory functions of the intestine) show the complex origin
of the fat present in the faeces after extirpation of the pancreas.
It cannot be taken as an exact expression of defective absorption
due to deficiency of the lipolytic enzymes.
Eat absorption in dogs with a complete fistula of the gall-
bladder was more particularly studied by Voit (1882), Eohmann
(1882), Fr. Miiller (1885), I. Munk (1890), He'don and Ville
(1897). The results obtained by these observers agree fairly well
together. Those of Munk deserve special attention. He compared
the absorption of different kinds of fats in a dog of 23 kilos., oper-
ated on 6 months previously by a biliary fistula. He found that
67 per cent pork fat (in a dose of 3'50 grms. to each kilogramme
of the animal) was absorbed, while only 36 per cent was absorbed
of mutton fat, which has a higher melting-point. Absorption was
increased if, instead of these neutral fats, the corresponding fatty
acids were administered.
The form in which the fats reappear in the dejecta is chiefly
that of free fatty acids (Eohmann, Miiller, Munk, He'don). Voit
alone assumes that the form of neutral fat predominates.
It is more important to determine the alterations in the diges-
tion and absorption of fat, when both pancreatic juice and bile are
simultaneously excluded from the intestinal canal, the former by
extirpation of the pancreas, the latter by fistula of the gall-bladder.
The effects of this double operation were studied by H6don and
Ville in their experiments on two dogs, which only survived the
operation 12 and 22 days. They found that the digestive dis-
orders, already conspicuous after removal of the pancreas, were
accentuated after the bile had been cut off. The two animals
became more voracious than when the pancreas alone was extir-
pated. They speedily exhibited a marked disgust for fat. After
some days the faeces showed bloody streaks, and the emaciation and
debility became excessive. In the last days of life the dejecta were
blackish (melena), and death occurred with symptoms of exhaustion.
284 PHYSIOLOGY CHAP.
To us, the most interesting fact is that under such conditions
fat absorption should still be possible. Analysis of the faeces
showed that non-emulsified fats (diet of bacon and meat) were
absorbed to an amount of 10 per cent ; finely emulsified fats (milk-
diet) were absorbed in quantities above 22 per cent. The greater
part of the fats eliminated with the faeces (78-90 per cent) appeared
in the form of free fatty acids, which were unmixed with soaps, or
mixed to a minimal extent only. There was thus a cleavage of
fats to an extent not less, but even somewhat greater, than that
which took place in dogs with a simple fistula of the gall-bladder,
which gives some idea of the fermentative activity of the intestinal
bacteria during the fat digestion. The putrefactive phenomena
(apparent in the foetid odour of the excrements), which increased
during the course of the observations, appear to be in ratio with
the cleavage of the fatty substances.
In explanation of the intestinal haemorrhage which hastens the
death of animals thus operated on, Hedon holds that bile and
pancreatic juice have a beneficent action upon the nutrition of the
intestinal mucous membrane ; but this is not the place in which
to discuss his hypothesis. The important point in his conclusions
is that the non-absorbed fats reappear in the faeces mostly in the
form of free fatty acids, with few or hardly any soaps. Hedon,
with little foundation, considers this fact to be an argument in
support of the theory that the cleavage of fats is not a necessary
condition of their absorption. We shall see that there is a better
interpretation of his significant discovery.
Another fact, which shows plainly that the glycerides in order
to be absorbed must first be decomposed, and then reconstituted
by synthesis after absorption, appears from the experiments of
Otto Frank (1894), which show that on feeding dogs with neutral
fats, or with fatty acids which have a higher melting-point than
that of the body (45° C.), they can be absorbed, and that a fat is
constantly present in the chyle, which melts approximately at
body temperature. On the other hand, it was shown by I. Munk
that after ingestion of spermaceti (palmitate of cetyl alcohol)
palmitin appeared in the chyle. The cetyl-palmitate therefore
splits up, and the palmitic acid combines with glycerol to form a
neutral glyceride. Nothing, however, is known as to the origin of
the glycerol required in this synthesis.
After the doctrine of fat absorption as an emulsion had been
overthrown, it still had to be decided whether the fats were
absorbed in the form of soaps, or of fatty acids, which, as we know,
are readily dissolved in bile, and specially in the bile acids (see
p. 220). From a series of exact experiments on the solubility
of fatty acids in bile (from ox, sheep, or dog) Moore and Rockwood
(1897) concluded that this was sufficient to explain the absorption
of alimentary fats in the form of free dissolved fatty acids. But
v INTERNAL EESTITUTIVE SECEETIONS 285
they denied that the whole of the ingested fat was absorbed in
this form. The results of their experiments rather led them to
conclude that the form in which fat is absorbed varies in different
species of animals ; although they maintained that the greater
part, if not the whole, of the fat is absorbed in a soluble form by
the epithelial cells. In this connection they noticed that when
fatty acids are dissolved in bile, the alkaline is transformed into
an acid reaction ; when dissolved in the filtrate from the intestinal
contents of the dog, the acidity increases. If, therefore, the intes-
tinal content has an alkaline reaction, the assumption that it
contains dissolved free fatty acids to any non-negligible amount
may be excluded. They further observed that the small intestine
of white rats was alkaline almost throughout its entire length
during fat absorption. In the dog, on the contrary, the lower
tract of the ileum only (as a rule) is alkaline, while the larger part
of the small intestine gives an acid reaction. In the contents of
the latter the dissolved fat is not present exclusively in the form
of free fatty acids, but is in the form of soaps as well, showing that
it contains more alkali than is required for combination with the
inorganic acids, and that this excess of alkali must be combined
with the fatty acids. In the last part of the dog's ileum, the con-
tents of which give an alkaline reaction like the whole of the small
intestine of the white rat, only soaps are present, in solution.
Thus in the white rat, according to Moore and Rockwood, the fat
is probably absorbed in the form of soaps; in the dog, part is
absorbed as fatty acid and part as soap, in variable proportions.
The importance of the formation of soaps, according to Moore
and Rockwood, lies in the fact that they assist the emulsification of
the neutral fats. Even if the fats cannot be absorbed in the form
of an emulsion it is easy to see how advantageous to digestion and
cleavage the emulsification of fat in the intestine must be : it is
then reduced to a state of fine division which presents a far larger
surface to the action of the lipolytic enzyme. Moore and Rock-
wood noted emulsification of fats in the intestine in 10 out of 16
experiments on dogs, although never in the degree of fineness and
stability characteristic of the milky emulsion present in the chyle.
In view of the experiments above described, on the effects of
extirpating the pancreas and diverting the bile, or of the two
operations together, as regards fat absorption, it appears to us that
other considerations may be added to the conclusions of Moore
and Rockwood as to the importance of soap formation. It is
evident that the soaps serve not only to emulsify the neutral fats,
and thus supplement the function of the lipolytic enzyme and the
bacterial ferments, but also to facilitate — probably to render
possible — the absorption of the digested fats. The waste fat met
with in the dejecta (much or little according to the different con-
ditions of experiment) always consists mainly of free fatty acids
286 PHYSIOLOGY CHAP.
and to a minor degree of soaps. This well-established fact in our
opinion authorises the conjecture that, as the epithelium of the
stomach is impermeable to hydrochloric acid, so the intestinal
epithelium is impermeable to the fatty acids, which can thus be
absorbed only in the form of soaps, i.e. in the alkaline vehicle of
the pancreatic juice, bile, and succus entericus.
Lombroso's observations on the reaction of the mucous
membrane stimulated by contact with fatty acids favours the
theory that fat is absorbed in the form of soaps.
As shown above (p. 130), he saw that on introducing fatty
acids dissolved in bile into a Vella's loop, a copious secretion was
induced, and renewed as often as the secretion collected was
reintroduced, so long as it contained enough non-absorbed free
fatty acid. In view of the quantity of secretion discharged
altogether by the loop, and its potential alkalinity, we see that it
is approximately what is required to transform the whole of the
fatty acid into soap.
Thus the fatty acid, even when completely dissolved, does
not appear to be absorbed as such : on the contrary, it evokes an
abundant intestinal secretion which tends to transform it into
soap. Soaps, however, are only present in very small quantities
in the faeces. How is it possible to interpret this phenomenon
otherwise than by assuming that the soaps have been absorbed,
and thus disappear from the secretion, while the fatty acid is
present because the intestinal epithelium refuses to absorb it,
probably by a kind of negative selection.
VI. The problem of Protein Absorption is no less complex.
In the first place, a question presents itself which it will be well
to solve as a preliminary. Is peptonisation, or the more or less
advanced hydrolytic cleavage of proteins, necessary to their
absorption ? Are the intestinal epithelia permeable only to
peptones and proteases, or to the natural proteins as well ? The
first view was sustained by Mulder (1858), and Meissner (1859),
and was adopted by many others, particularly by Hermann.
Starting from the notion that absorption is a process of diffusion,
they held the peptonisation by which proteins are transformed
from indiffusible into diffusible bodies to be indispensable for their
absorption.
The first critics of this theory, which found much favour, were
Briicke (1859-69) and Diatonow (1867-68), who asserted that the
natural proteins in solution (colloidal) are with few exceptions
capable of traversing the wall of the intestine without altera-
tion by the proteolytic enzymes. Better experimental evidence
for this theory was brought forward by C. Voit and Bauer (1869).
In a living dog they introduced protein into an intestinal loop
(previously washed and isolated by ligatures), in the form of
solutions of myosin, syntonin, and egg-albumin, and found them to
v INTEKNAL KESTITUTIVE SECKETIONS 287
be absorbed in 1-4 hours, without showing the least trace of
proteose or peptone previous to their disappearance.
In a subsequent study of the absorption of different alimentary
substances introduced per rectum into the large intestine (a method
that found wide application in clinical medicine) Eichhorst (1871)
found that in addition to myosin and syntouin the protein of
milk and metaprotein were capable of absorption, without any
trace of peptonisatiou, in the large intestine.
The same fact was observed by Czerny and Latschemberger in
man, in a case of fistula of the sigmoid flexure, which allowed
perfect washing out and disinfection of the rectum, so as to
exclude all intervention of proteolytic enzymes and bacteria.
Nencki and his pupils (1891) arrived at the same results, experi-
menting on man in a similar case of fistula of the large bowel.
Their results show that 70 per cent of dissolved metaprotein can
be absorbed in a day.
These same proteins, injected directly into the veins, are
eliminated in the urine in the form of urea only. They are there-
fore utilised by the body, and require no digestive alteration to
fit them for assimilation. It is otherwise with ovalbumin,
caseinogen, haemoglobin, and gluten, which substances, if injected
into the blood, are eliminated unchanged in the urine.
Ovalbumin must therefore be transformed into syntonin
by the action of the gastric juice, before it can be utilised. In
fact, when introduced per rectum in the natural state it is not
absorbed (Bauer); ingested by the mouth in large quantities it
can be absorbed, but produces albuminuria (Briicke). Directly
sodium chloride is added, however, it becomes absorbable, though
very slowly, and can be utilised (Voit, Bauer, Eichhorst, Huber).
It has not yet been discovered why the addition of sodium
chloride renders the mucous membrane of both large and small
intestine permeable to egg-albumin, which in itself is inabsorbable.
All explanation of the fact is wanting, but it has been positively
confirmed and established. Baldi (1896), in a series of very clear
and simple comparative experiments, showed that solutions of
commercial peptone (which consists principally of proteoses) are
also absorbed more rapidly from a Vella's loop, if a little sodium
chloride be added.
Caseinogen is normally refractory to absorption owing to the
coagulation it undergoes in the stomach from the enzymatic
action of the chymosin of the gastric juice ; hence it can only be
absorbed after decomposition into syntonin and nuclein. Haemo-
globin, too, is broken up by the action of the gastric acid into
albumin and haematin : the first can be absorbed as such, the
second is eliminated for the most part with the faeces, and is only
to a minor extent utilised by the liver in the formation of bile-
pigments.
288 PHYSIOLOGY CHAP.
This evidence that the greater part of the soluble proteins can
be absorbed as such, or after slight changes, radically modifies our
ideas as to the importance of the peptonisation effected by the
gastric, and still more by the pancreatic, juice in the consumption
of alimentary protein. These juices obviously render soluble,
and therefore absorbable, the proteins introduced in the solid state,
and they also split up non-absorbable protein, and liberate the
utilisable protein-groups of the molecules : but soluble proteins can
be absorbed and utilised as such, without any previous hydrolytic
cleavage into proteoses and peptones.
There is, however, no doubt that a considerable part of the
soluble proteins do undergo proteolytic cleavage previous to
absorption. When we reflect that part of the potential energy of
the natural proteins is wasted in their cleavage into proteoses and
peptones, the utility of this process is hard to understand. But it
should not be forgotten that proteoses and peptones (from their
physical and chemical properties), are more easily and promptly
absorbed by the intestinal epithelia than are natural or scarcely
altered proteins. In this lies the utility of scission and subdivision
of the latter, which is carried farther or arrested as required,
particularly in proportion as they are introduced in excessive or
scanty quantities, and as the proteolytic enzymes are abundant or
defective.
The medical use of feeding debilitated persons and invalids
on proteoses or peptones may be justified by their ready absorp-
tion. But under physiological conditions, such a prescription for
utilising the alimentary principles is not only unnecessary, but
is neither economical nor advantageous in comparison with a diet
of natural proteins, as was clearly proved by Horton-Smith (1891).
The fact that proteoses and peptones are capable of replacing
natural protein under all conditions of nutrition was clearly
demonstrated by the experiments of Maly and Plosz (1874).
The former fed a pigeon, the latter a dog, very satisfactorily for
some time upon a diet in which proteoses and peptones replaced
the natural proteins. The same successful results were obtained
in a striking manner by Zuntz (1885), Pollitzer (1885), Gerlach
(1891), and Pfeiffer (1885), the last of whom experimented on
himself for ten days in succession.
These results showed the suggestion of some authors (Briicke,
Voit, and A. Fick in particular) to the effect that peptones, though
absorbable, cannot be assimilated by the tissues, and that natural
proteins alone can compensate for tissue waste, to be unfounded.
We may conclude that the protein stored up in the tissues conies
from two sources : from the dissolved proteins absorbed as such,
and from the products of their digestion, i.e. proteoses, peptones,
and ammo-acids. It is difficult to determine how much of the
ingested protein is absorbed unchanged, and how much after
v INTERNAL RESTITUTIVE SECRETIONS 289
undergoing more or less advanced peptonisation and hydrolysis.
Schmidt -Miilheim's researches in this direction are not very
convincing. It seems probable that the degree of peptonisation
and hydrolytic cleavage into amino-acids of the proteins varies
considerably within wide physiological limits.
With this question we must associate the effects of total
or partial removal of the pancreas, in relation to the absorption
and utilisation of alimentary protein. According to Minkowski
and Abelmanu (1890), a dog wholly deprived of its pancreas may
absorb and utilise on an average 44 per cent of the flesh ingested ;
when the extirpation has been incomplete it may even make use
of 54 per cent. When a little pig's pancreas is fed to the animal
along with the meat, the amount of protein lost with the faeces
is conspicuously diminished. According to Landmeyer's latest
experiments (1895), 62-70 per cent of the proteins can be utilised
after incomplete ablation of the pancreas. Nothing definite
can, however, be concluded from this fact as to the extent under
normal conditions of the peptonisation of ingested proteins and
their cleavage into amino-acids. It is certain that a considerable
portion of them must be subjected to this process not only to
accelerate absorption, and thus increase the amount utilised by
the body, but also, by means of the molecular aggregates repre-
sented by the amino-acid group, to make possible the synthetic
constitution of the complex proteins which are specific to organisms
of different species or genera.
The process by which the proteoses, peptones, and amino-acids
are utilised by synthetic processes is very remarkable. They are
largely regenerated into natural protein (probably into serum-
albumin) during their passage through the mucous membrane, by
the anabolic activity of the epithelium. The experimental data on
which this important conclusion rests are numerous and agree
well together.
(a) Proteoses and peptone are never found in the blood or
lymph, even when these fluids are examined during absorption,
after an abundant digestion of proteins. Schmidt-Miilheim and
Hofmeister stated that peptone could be detected in blood-serum in
a maximum amount of 0'02-0'05 per cent, but more exact experi-
ments subsequently undertaken by Neumeister (1888) excluded
even this small amount of peptone. Under the best conditions
of experiment, the biuret test is always absolutely negative, both
with lymph and with blood-serum.
(6) When proteoses and peptone are injected directly into the
blood, they immediately disappear from it (Fano), and pass into
the urine as bodies foreign to its normal composition (Hofmeister,
Neumeister). If a considerable quantity be injected, they induce
toxic phenomena and modify the composition of the blood by
rendering it incoagulable, which causes an enormous lowering of
VOL. II U
290 PHYSIOLOGY CHAP.
arterial blood - pressure, with ecchymosis of various organs
(Schmidt - MiUheim, Fano, Kiihne and Pollitzer, Neumeister,
Shore, Salkowski). It is therefore necessary that the proteoses
and peptone absorbed from the intestine shall, before they
penetrate into the blood and lymph, be modified until they lose
all toxic action.
(c) The organ which effects this transformation or regeneration
is not the liver, as was formerly supposed, because the portal blood
contains no more peptone than the rest of the blood. Moreover,
if blood containing peptone be circulated through the vessels of
the surviving liver, freshly excised from the animal, the peptone
does not disappear nor even sensibly diminish in the circulating
blood. The same result is obtained if peptone be injected into a
mesenteric vein, i.e. in the direction of the liver, in a living
animal, the blood of the hepatic vein being then examined
(Neumeister). The same appears, again, on injecting peptonised
blood by the splenic artery, so that it must pass through the
spleen and the liver in succession (Shore). This last experiment
shows that the spleen is also incapable of converting peptone into
natural protein.
(d) It was G. Salvioli (1880) who first, in Ludwig's laboratory,
demonstrated that proteoses and peptone are synthetised into
natural protein in passing through the intestinal walls. He
isolated a loop of intestine from a recently killed dog, closed the
ends by ligatures, and introduced a gramme of dissolved peptone.
Artificial circulation was then established through the arterial
and venous vessels of the loop, by which perfect vitality was
maintained, as shown plainly by the peristaltic movements.
After four hours' circulation in a glass chamber warmed to 37°-
40° C., he found only about half a gramme of coagulable protein,
and hardly a trace of peptone in the intestine. No peptone was
found in the circulating blood. If it had been added previous to
circulation it was found present in the same amount at the close
of the experiment. Evidently, therefore, the peptone absorbed
from inside the loop disappeared while traversing the intestinal
wall,- before it could reach the blood. Under the conditions of
this experiment, however, a part of the peptone is decomposed
into amino-acid previous to absorption.
(0) Hofmeister (1885) showed that the mucous membrane of
the stomach and intestine is the sole tissue (except the spleen) in
which the presence of peptone can be detected during digestion.
But the peptone present in the gastro-intestinal mucous membrane
rapidly undergoes conversion. If two equal parts of stomach or
intestine are taken from a dog killed during digestion, the first
part being thrown into boiling water, the second kept for some
time at 40° C. before immersing it, peptone will be found in the
former, while there is none left in the latter. In this the peptone
v INTERNAL EESTITUTIVE SECRETIONS 291
disappears, not by decomposition, but by synthetic regeneration
into natural protein by the vital activity of the cells of the
mucous membrane. The peptone does not in fact disappear from
the mucous membrane if this be plunged not into boiling water,
which destroys the enzymes also, but into water at 60°, which
destroys the vitality of the cells without affecting the enzymes.
According to Neumeister (1890) considerable amounts of peptone
and proteose can be converted in a short time, when they are
mixed with dilute blood and fragments of intestine from a freshly
killed animal are thrown in, the blood being then agitated with a
gentle current of air, so that every part of it comes into contact
with the mucous membrane of the intestine.
Fano (1881) showed that after injecting peptone and proteoses
into the blood they disappeared rapidly, while the specific gravity
of the erythrocytes increased, which supports the hypothesis that
the erythrocytes are the active agents in regenerating the pep-
tones, or some of them at least, the peptone being dehydrated and
split up with conversion into globulin, by the potassium salts that
predominate in these cells, and by the presence of oxyhaemoglobin.
He therefore thinks it probable that the more or less peptonised
proteins that penetrate into the blood from the alimentary canal
may be partially absorbed and stored up by the erythrocytes, as
reserve materials which are subsequently poured into the plasma
to compensate for the losses it has sustained.
Hofmeister (1885), on the other hand, supported the hypothesis
that the active agents in the regeneration of proteoses and
peptones and in their transport in the blood are represented by the
leucocytes of the adenoid tissue of the villous mucous membrane,
which accumulate there during digestion, and insinuate themselves
through the interstices, and perhaps also into the interior of the
columnar epithelial cells. He thus attributes to the leucocytes,
in the absorption of peptones from the intestine, a function
similar to that which the erythrocytes perform in the absorption
and transport of oxygen from the lungs to the tissues. Both
Fano's and Hofmeister's hypotheses were, however, subsequently
contradicted by various facts; notably by the experiments of
Shore, who saw that a small quantity of peptone (5 cgrms.) injected
into a peripheral lymphatic of one of the posterior limbs reappeared
in the lymph collected from the thoracic duct in 30 minutes.
On the other hand, we know that peptone does not completely
disappear when it is added in small quantities to freshly extracted
blood or lymph, although the former contains numerous erythro-
cytes, the latter numerous leucocytes, which long survive under
favourable conditions of temperature.
There can therefore be no doubt that the synthesis of the
proteoses and peptones is effected by the vital activity of the
epithelial cells of the mucous membrane.
292 PHYSIOLOGY CHAP.
It has been stated that the proteoses and peptones can be
synthetised into serum-albumin in the intestine, and also in the
stomach, by simple contact with the living epithelial cells, i.e.
previous to absorption. Von Ott (1883) observed in the abdominal
and intestinal cavity of recently killed rabbits, as also in the
stomach of living dogs, that serum-albumin can be formed after
introducing commercial peptone (which consists largely of
proteoses). To prove that this was a true regeneration into
serum-albumin he employed not only chemical reagents but
also a physiological reagent, i.e. the frog's heart, excised and
attached to Kronecker's apparatus. The heart did not beat
when tilled with a solution of proteoses or peptone, and recom-
menced its beat when filled with the same solution regenerated
by contact with the gastric or intestinal mucous membrane.
Von Ott's results were confirmed and extended by Julia Brinck
and N. Popoff in Kronecker's laboratory (1889); they used
Vella's loop of intestine for the regeneration of the proteose and
peptone.
That the synthetic reconstruction of the coagulable protein is
the work of the living epithelial cells is proved by the fact that
the phenomenon does not occur when proteoses and peptone are
brought into contact with the mucous membrane of the intestine
or stomach after the death of the cells (20 min. after killing the
animal). In this case (if the body is placed in a chamber
regulated at 37°-40° C.) auto-digestion of the mucous membrane
may take place, but there is no synthesis of the proteoses and
peptone introduced. J. Brinck further found in the contents of
the intestine a micrococcus capable of the same synthetic function
as the epithelial cells, to which she gave the name of Micrococcus
restituens.
Granting the accuracy of these interesting phenomena, they do
not seem to us adequate to prove that proteoses and peptones
are regenerated into serum-albumin by simple contact with the
living epithelia, previous to absorption. If this be admitted,
there can be no advantage in the proteolytic process, which
facilitates or accelerates absorption. It seems to us more logical
and simpler to assume that part of the protein formed synthetically
by the cytoplasm of the epithelial cells is poured back into the
intestine with the succus entericus or gastric secretion from the
glandular crypts of the intestine and stomach respectively. It is
now known as a fact that succus entericus always contains a
certain amount of protein (0'5 per cent according to Quincke,
according to Thiry, Pregl, and others a somewhat larger proportion).
And Mme. Schumowa-Simanowskaia demonstrated that pure
gastric juice obtained from a gastric fistula with sham feeding
always contains a certain amount of protein (0'13-0'18 per cent).
We regard it as probable that the coagulable protein found by
v INTEKNAL EESTITUTIVE SECEETIONS 293
Salvioli in the excised loop of intestine into which peptone only
had been introduced, has the same secretory origin, i.e. it is derived
from succus entericus secreted during the absorption and subse-
quent regeneration of the peptone.
The disappearance of the peptone artificially introduced into
the loop of intestine may therefore be the result of a conversion,
not into larger complexes, but (at least partially) into simpler
crystallisable complexes (ammo-acids).
We already know from the work of Kiihne (p. 211) that
the protracted action of trypsine upon peptone may result in very
simple products. Neumeister (1890), who observed the disappear-
ance of peptones from the blood diluted with peptone solution in
which he had placed freshly excised fragments of intestine, came
to no definite conclusion in regard to the disappearance of
peptones by conversion into more complex products ; but he
brought forward the other possibility, viz. the formation of amino-
acids, already suggested by Briicke, by Voit, and particularly by
Fick, since he was able to show the presence of leucine and
tyrosine, although only in small quantities.
Capparelli (Catania, 1899) suggested the same account of the
conversion of peptone in the intestine. He introduced a solution
of commercial peptone into an empty loop of intestine in a dog
that had fasted 1-3 days, after tying it at the ends and isolating it
from the mesentery so as to prevent absorption by the blood, after
which it was replaced in the stomach. On testing the fluid after
1-1| hours the peptone had disappeared. The same occurred in
vitro on mixing shreds of intestinal mucous membrane with peptone
solution, as also with a mixture of various digestive enzymes, or
with trypsin alone. In all these cases he found that the products
of peptone conversion were highly soluble in water, insoluble in
alcohol, dialysible, with a rotary power different from that of the
original peptone solution. He concluded that he was dealing with
a complex simpler than peptone, which he was, however, unable to
identify.
0. Cohnheim has recently formulated more concrete opinions
on the same subject. As we saw on pp. 127, 212, he found that the
intestinal mucous membrane actually contained a special enzyme
which he called erepsin, which has this very property of breaking
up the proteoses and peptones into smaller complexes (arnino-
acids). Neumeister and Capparelli may both be regarded as the
immediate precursors of the discovery of erepsin.
According to Kiihne, Cohnheim, and others, absorption of
proteins takes place after their more or less complete conversion
into aniino-acids. Part of these are synthetised by the mucous
membrane of the intestine, part, on the contrary, which are
absorbed unchanged, are directly consumed by the tissues, or
undergo within their depths the synthetic processes by which
294 PHYSIOLOGY CHAP.
they are fitted to repair the losses that continually occur in the
individual cells.
This does not, however, exclude the absorption of protein, as
such, more particularly of peptone, i.e. before the latter breaks
up into ammo-acids. In fact, after herbivora (rabbits, guinea-
pigs) had been kept for some time on a milk diet, Hamburger
observed the presence of the so-called precipitine in the blood
(the " biological " reaction). M. Ascoli, Vigano, and Moreschi
employed the same method to determine the fate of the ali-
mentary proteins. It is based on the property by which blood
serum is able to precipitate foreign proteins, against which it has
been immunised by repeated subcutaneous injections. Kaw egg-
white or roast chicken was fed to dogs, by means of the sound, the
reaction of the blood and lymph (from a thoracic fistula) to rabbit-
serum, previously immunised to these proteins, being tested before
and after they were introduced (the proteins being precipitated by
the serum). In consequence of this diet the lymph (less constantly
the blood) of the animal experimented on, was thrown out by
serum which had been immunised to the proteins fed. From this
Ascoli concluded that the highly complex atomic groups derived
from the proteins (if not the proteins themselves, unaltered) which
cause the biological reaction of precipitation, are able to pass
through the gastro-intestinal wall and penetrate to the lymphatic
system, without previous reduction to crystallisable products.
VII. From all that has been said of the absorption of the
different groups of food-stuffs in the gastro-intestinal canal, and the
chemical changes that some of the absorbed products of digestion
undergo in consequence of the activity of the epithelial cells, it
is clear that the mechanism of these marvellous processes is
not essentially different from, certainly not less complex than,
that by which each living cell or independent elementary organism
draws the alimentary principles required for its nutrition and
development from the environment in which it lives, and then gives
off the products of its anabolic and katabolic activity.
The special organ of intestinal absorption is the villus, which
in view of the complex of epithelial cells with which it is clothed,
may be regarded as an extrajlected glandular crypt, in which the
epithelia do not absorb the lymph from the end which is attached
to the basement membrane, but take up the food-stuffs (whether
modified or not by the digestive process) from their free end, at
the striated border. The absorbed materials which are partially
modified by the metabolic activity of the cells are not poured
outwards as in the intraftected crypts, but are emptied into the
lymph sinuses of the adenoid tissue of the villi, whence they make
their way by the blood capillaries through the portal vein to the
liver, or by the central lymphatic, which leads to the thoracic duct.
P. Mingazzini (1900) gave new support from the histological
INTERNAL EESTITUTIVE SECRETIONS
295
standpoint to this physiological theory, in which the villus of the
intestine is regarded as an inverted glandular organ of internal
secretion. He examined the intestinal villi of various vertebrates,
but up to the time of his death had only published his observations
on the small intestine of the fowl, which seemed to him the
clearest and most important.
When examined in different phases of digestion the villi, he
says, may present two entirely
different aspects, according as they
are in the resting or in the actively
absorbing state. In the first case
all the epithelial cells of the villi
are regular, and approximately equal
in form and height, with nuclei
that are always at the same level,
i.e. toward the middle or inner
third of the cell, and protoplasm
that stains more intensely towards
the external free end, less intensely
towards the basal portion beneath
the nucleus (Fig. 94).
During its functional work, the
villus looks quite different. "While
the stroma of adenoid tissue, mingled
with bundles of plain muscle cells,
preserves the form and dimensions
of the resting state, the epithelial
covering undergoes profound modi-
fications, which entirely alter the
aspect of the villus as a whole
(Fig. 95). During the first phase
two distinct cellular zones begin
to be differentiated : an outer,
granulated and readily stainable FIG. 94.— vnius of small intestine of fowl.
j • i v -i Resting state. (P. Mingazzini.) c, striated
zone, and an inner, hyaline, less
granulated zone, which stains pale
yellow with picric acid. In a
more advanced phase of absorption,
the inner zone grows out beyond
the nucleus, which tends to a conspicuous lengthening of the
cells, so that the nucleus is pushed into the outer third of the
body of the cell. Finally, in a third phase, the hyaline portion
gradually liquefies or vanishes by internal absorption, till at last
only the outer zone of the epithelial cells is left, at the base of
which the nucleus is found almost in contact with the basement
membrane.
As shown in the figure, different parts may be distinguished
-vl
border of epithelium ; nc, nuclei of
columnar epithelium ; I, leucocytes
scattered in cytoplasm of epithelium ;
ml basement membrane of epithelium ;
cv, adenoid.tissue of villus which also con-
tains muscle fibres ; vl, central lacteal.
296
PHYSIOLOGY
CHAP.
in the same villus, showing epithelia in the first, second, or third
phase of the process of absorption and internal secretion of the
absorbed products. It is usually the epithelia of the apex of the
villus which show these changes most conspicuously; along the
lateral walls of the villus they are less obvious, and are minimal
towards its base.
According to Mingazzini, the stroma of the villi also presents
FIG. 95. — Villus of small intestine of fowl during absorption. (P. Mingazzini.) Lettering as in
previous figure. In the apex of right side of villus particularly the columnar cells have
become elongated and exhibit a zone external to the nucleus (zs) that stains deeply, and an
internal hyaline zone (zj) which contains the absorbed substance. At the apex of the villus
the inner epithelial zone is transformed into a granular substance (si).
different aspects in different phases. In some cases it seems to
consist of a compact tissue ; in others, on the contrary, of loose
tissue. In the former it is regular in form, and of small dimensions;
in the latter the form is not very regular, and the dimensions are
larger (Fig. 96). It is possible in the last case that the villi may
be swollen owing to the chyle poured out by internal secretion
into the lymph spaces of the adenoid tissue, before it reaches the
central lacteal. The leucocytes packed between the epithelial
cells are perhaps destined to function after the latter have dis-
charged their internal secretion.
These observations of Mingazzini gave rise to much discussion
v INTERNAL KESTITUTIVE SECKETIONS 297
both in Italy and abroad : some authors (as Drago, 1900 ; Renter,
1901 ; Kina Monti, 1903) agreed with his conclusions. Many,
however, hold the opposite opinion (Bezzola, 1901 ; Arcangeli, 1905 ;
Demjanenko, 1909) ; so that on the whole the theory of absorption,
considered as an internal secretion, is not, however well established
physiologically, sanctioned by histological evidence, as is the case
for other secretions.
Fit;. 9(3.— Villas of small intestine of fowl in a more advanced stage of absorption and internal
secretion. (P. Mingazzini.) Lettering as in previous figure. At the apexfof the villus the
internal secretion of absorbed substances has already taken place, so that the epithelial cells
are reduced to their minimal size. To the left, a sort of lobe projects, in which there is a
maximal accumulation of the granular substance secreted by the epithelia. The stroma or
adenoid tissue of the villus is compact below, and looser above, and swollen by the penetration
of chyle between its fibres. Here the nuclei appear to be farther apart than below.
The fats secreted by the columnar epithelial cells must pass
from the labyrinthine spaces of the adenoid tissue of the villus
into the central lacteal, and the carbohydrates and proteins mainly
into the interior of the capillary network of the villus. The
mechanism of this penetration has not been cleared up by direct
experiment, and we can only reconstruct this important process
by analogy.
In regard to the passage of fat from the labyrinthine spaces
to the interior of the central lacteal, we may assume that the
epithelioid cells which form the wall of the latter leave lacunae
298 PHYSIOLOGY CHAP.
or stomata, or permit the occasional formation of clefts in the lines
of junction, through which the minute fat droplets can pass easily.
It must, however, be stated that in chyle the fat is found in
a highly fractional form (sometimes known as the molecular
basis'), while in the cytoplasm of the columnar cells, and also in
the adeuoid reticulum that surrounds the central lacteal, it appears
in the form of globules of various sizes. We are ignorant of the
mechanism by which this extremely fine division and conversion
of the fat emulsion into the molecular basis of chyle takes place,
but it seems reasonable to suppose that it occurs at the moment
of passing into the lacteal, i.e. that the fat globules are altered
and broken up in penetrating through the very fine pores that
exist or are formed between the junctions of the epithelioid cells.
Hofmeister's notion that the leucocytes which accumulate in
the villi during absorption convey the fat into the lacteal must,
as already stated, be abandoned. Two facts in particular tell
against it. After administration of magnesium sulphate, which
produces a cathartic effect, i.e. opposed to absorption, an extra-
ordinary number of leucocytes accumulate in the villi, although
there is not and cannot be any fat absorption. On the other hand,
they are entirely absent from the villi of a sucking puppy,
although there is a marked passage of fat into the chyle (Foster).
It is evident that great importance in the penetration of fai
into the lacteals attaches both to the passive compression of the
villi due to the peristaltic movements of the intestine (Hamburger),
and to the active movements of the villi induced by the (probably
rhythmic) contraction of the muscle cells, with which the areolar
tissue of the villi is well provided. According to Briicke, the
muscles of the villi act during contraction like a pressure pump,
which empties the contents of the lymph spaces of the stroma into
the central lacteal, and the latter into the subjacent lymphatics,
which are provided with valves. The valves hinder a reflux
during the subsequent relaxation or expansion of the muscles, and
thus indirectly allow the lymph sinuses to refill with new material
absorbed and secreted by the columnar epithelial cells. Since the
muscle bundles have a direction predominatingly parallel to the
long axis of the villi, Briicke supposes that during contraction
the villi shorten and empty by positive pressure, while during
relaxation they lengthen and expand by negative pressure. But
it is possible to conceive the mechanism differently. According
to Heidenhain the villi shorten and thicken during contraction, so
that the central lacteal dilates. During relaxation the villi
lengthen and become thinner, in consequence of which the central
lacteal is constricted by compression, and evacuated. However we
conceive of the phenomenon, it is certain that a rhythmical con-
traction and expansion of the villi must favour (if it does not
absolutely initiate) the movement of the regenerated products
v INTERNAL RESTITUTIVE SECEETIONS 299
absorbed from the intestine, both into the lacteals and the blood-
vessels.
As regards the penetration of sugar and protein, we cannot
tell why these substances should under ordinary conditions be
absorbed, if not exclusively at least to a predominating extent,
by the blood capillaries of the villus. The mechanism of this
penetration also is unknown to us by direct experiment. It is
probably a process of transudation identical with that which gives
rise to the formation of lymph (see Vol. I. p. 523 et seq.}. The
difference is that while in the formation of lymph, transudation
takes place from the interior of the capillaries into the lymph
sinuses, in the absorption of chyle it occurs from the lymph
sinuses to the interior of the blood capillaries of the villi. We
have seen that transudation consists of two well-known physical
processes, diffusion and filtration. The greater concentration of the
food-stuffs of the chyle collected in the meshes of the reticuli of
the villi, as compared with that of the constituents of the blood
that incessantly courses through the capillary network, certainly
presents a condition favourable to endosmosis. On the other
hand, the pressure due to the contraction of the muscles of the
villi must favour filtration through the blood capillaries from
without inwards.
VIII. We have seen that while the products of the proteolytic
and lipolytic processes are regenerated during absorption into
natural proteins and neutral fats by the synthetic activity of the
columnar epithelium of the intestine, the digestive products of the
carbohydrates which pass through the intestinal wall penetrate
almost entirely by the blood vessels of the villi to the portal system,
and are, almost without exception, carried to the liver in the form
of grape sugar or glucose. According to Pfliiger, part of the
glucose that penetrates into the blood may, instead of remaining
there in the free state, enter into chemical combination with the
proteins, or the lecithin with which it forms jecorin. We have
seen elsewhere (Vol. I. p. 130) that the amount of glucose
normally present in blood plasma varies, according to Otto, from
(HO-015 per cent, and only exceptionally rises to 0*30 per cent,
or a little over. This proportion of glucose in the blood is wholly
independent of the nature of the food. Two facts may, however,
now be considered well established, from the results of numerous
analyses of the blood, arrived at by different observers : —
(a) After a meal rich in starchy and saccharine substances, the
sugar content of the portal blood reaches its maximum, while in
the blood of the hepatic veins it remains normal.
(6) During fasting, the sugar content of the blood in the
hepatic veins is somewhat higher than that of the portal blood,
which is minimal.
The first fact leads us to admit that the sugar absorbed from
300 PHYSIOLOGY CHAP.
the intestine after digestion is stored up in the liver : the second
that the liver returns the accumulated sugar to the blood by
internal secretion.
Thus we are brought back to the Liver, that giant gland which
we considered in the last chapter merely as the organ of bile
secretion, while admitting this to be neither the principal nor the
most important of its functions.
Magendie (1816) was the first who demonstrated experimentally
that the system of intestinal veins which form the roots of the
portal system, and to which Bichat drew the attention of
physiologists, is capable of absorbing the substances introduced
into the intestine — a fact denied by John Hunter. One of
Magendie's crucial experiments was as follows : —
He tied all the lymphatics of a loop of intestine isolated
between two ligatures; next, he tied all the arteries and veins
with the exception of one artery and vein, of which he removed
the adventitia for a certain distance to make sure that no lymph
vessel had been left ; lastly, he injected a decoction of nux vomica
into the loop. After 6 minutes, strychnine poisoning set in with
great intensity, showing that absorption had taken place through
the roots of the only intestinal vein remaining. The later experi-
ments of Se"galas and of Tiedemann and Gmelin, confirmed
Magendie's results, and established the importance of the
intestinal veins in intestinal absorption.
But it was Claude Bernard who fully vindicated the claims of
the liver, which Bartholin had disallowed. In 1849 he announced
that animals, like plants, have the power of forming sugar
independent of the nature of the food, and that this new function
resides in the liver, which is therefore the seat of a double secretion ;
the one external, of bile ; the other internal, of sugar.
In studying the course of the ingested sugar, as it passes
through the body, Bernard sought for it in the venous blood
coming from the right heart and the arterial blood coming from
the left carotid, on the assumption that it was decomposed by the
lungs. He observed that the blood of the right heart contained
sugar, not only when it was extracted from a dog fed on sugar,
but also when the animal was kept on a flesh diet. From this he
concluded that there must be an organ in the body capable of
forming sugar, independent of what was ingested, and that this
organ was the liver, because extract of liver was able to reduce
Bareswill's reagent and gave rise to alcoholic fermentation, which
did not occur with extracts of the other organs.
In order to demonstrate that the liver really manufactures
sugar during its life, it was necessary to prove that the blood
flowing from the liver contained more sugar than the blood which
entered it. In 1850 Schiff, who found a certain amount of sugar
in human blood, and in that of animals from the slaughter-house,
v INTEENAL KESTITUTIVE SECKETIONS 301
argued that this substance must be generally diffused in the body
like urea, and that its production could not be localised in a single
organ.
In continuation of these researches Bernard (1850) demonstrated
the presence of sugar in the liver of mammals, birds, reptiles,
fishes, and molluscs. He further proved that the blood of the
hepatic veins invariably contained sugar during digestion ; that it
contained less when digestion was completed ; hardly any after a
long fast. After prolonged feeding of dogs with flesh, he estimated
the sugar content of the intestine and the portal blood, and found
none perceptible to reagents ; on the other hand, there was a con-
siderable amount in the blood of the hepatic veins and the liver.
In order, however, to establish Bernard's theory of hepatic
glycogenesis (to which objections were raised by Figuier, Sanson
and Colin) upon a solid basis, it was necessary to exclude the
possibility that the sugar had been carried by the portal blood, the
liver merely having the task of storing it up and accumulating it,
as it does with other substances (arsenic, antimony, mercury, etc.).
The fundamental experiment which Bernard devised in 1855 for
this purpose, consisted in extracting the liver from the abdominal
cavity and irrigating it by the portal vein with a continuous
current of water. After 40 minutes' irrigation, he excised a bit
of the liver, boiled it, and found no sugar in the extract. After
24 hours the remainder of the liver was extracted, and was
found to contain much sugar. From this Bernard concluded
that the liver contains a material from which sugar is formed.
He further concluded that contact with the air is favourable to
the formation of new sugar, while it is on the other hand checked
by boiling. Since sugar can be formed in the liver of animals
fed exclusively on a flesh diet, Bernard concluded that it is manu-
factured in the liver at the expense of the nitrogenous protein, by
a process of fermentation.
Soon after, however, and almost simultaneously, Hensen
(December 1856) and Bernard (March and June 1857) extracted
from the liver glycogen or animal starch, a substance similar to
vegetable starch or rather to dextrin, which is readily converted
into sugar by the influence of the salivary or pancreatic enzyme,
as the starch of barley is converted into sugar during germination
by the action of diastase. To separate glycogen, the liver of a
well-fed animal must be excised, chopped up, and steeped in
boiling water. After boiling, the fragments of liver are pounded
in a mortar to a paste, which is then extracted, neutralised,
filtered, and boiled again to get rid of the proteins, when an
opalescent extract is obtained, which is milky in appearance, and
remains unchanged by repeated filtration. On adding iodine the
extract stains red like erythrodextrin ; on heating the colour
disappears, to reappear on subsequent cooling. Trommer's test
302 PHYSIOLOGY CHAP.
shows that the solution contains very little sugar. On adding
saliva or pancreatic extract, as also on boiling with dilute mineral
acids, the opalescence and the iodine reaction disappear, while
Trommer's test show's the presence of much sugar.
Briicke obtained glycogen in the pure state by perfecting this
method.
Estimation of Glycogen (Pfliiger). — The liver of an animal is minced and
boiled for 2-3 hours in the water-bath with 30 per cent caustic potash. The
solution is then cooled, with the addition of 2 parts water and 4 parts
alcohol (96 per cent). The mixture is allowed to settle, filtered in a porcelain
filter, washed with a mixture of one volume 15 per cent potash and alcohol
at 96°, and then with alcohol alone at 96°. The precipitate is dissolved in
boiling water. The filtrate is boiled separately to extract the residue of
glycogen. The solution is then neutralised, and refiltered, after which
hydrochloric acid is added till the concentration is 2'2 per cent. It is then
boiled for 3 hours ; when cooled the liquid is neutralised and filtered. The
glucose is then estimated : 1 gnu. glucose corresponds to 0'927 glycogen.
After the discovery of glycogen, Bernard modified his original
view of the direct formation of sugar in the liver. The glyco-
genesis is indirect, i.e. is a function consisting of two quite distinct
processes, the first being the formation of the glycogenic substance
in the living hepatic tissue (amylogenesis'), the second the conversion
of glycogen into sugar by a ferment, which is probably contained
in the blood (glycogenesis proper}.
To Bernard's statement that the liver normally, i.e. during
life, manufactures sugar from glycogen, and discharges it by
internal secretion into the hepatic veins, Pavy (1861) objected that
glycogenesis is not a normal function of the liver, but a post-mortei
phenomenon. On drawing off the blood of a living animal from
the right heart with a catheter, he found that it contained hardly
a trace of sugar, while the same blood, collected after the death of
the animal, usually contained a considerable amount. On excising
fragments of liver from a live dog, and plunging them directly
into boiling water, he found mere traces of sugar in the extracts.
Sitter, MacDonell, Schiff, Lussana (1862-66) repeated Pavy's
experiments with variations, but always obtained the same results.
The living normal liver either contains no sugar or a small
quantity only. They concluded that the liver only forms
when the hepatic cells are injured by neuroparalytic hyperaemi*
by heterogeneous substances injected into the vessels, post-mortei
decomposition, etc. The formation of glycogen is an essential!}
physiological process; its conversion into glucose is an abnorrne
or dissimulatory post-mortem phenomenon.
As against this conclusion and in favour of Bernard's theor
are the conclusions of Dalton (1871), who found that the living
liver contains G'2-0'4 per cent sugar, a quantity in excess of that
usually found in the blood. Eecent analyses, moreover, have
v INTERNAL RESTITUTIVE SECEETIONS 303
demonstrated indisputably that there is a marked difference
between the sugar content of the blood from the portal and that
from the hepatic veins, without even temporary arrest of the
circulation through the liver. While the portal blood on an
average contains 0-1 per cent sugar, that of the hepatic vein
contains on an average 0'2 per cent. This fact seems to us to
decide the controversy in favour of sugar production in the
normal living liver.
When we consider the large amount of blood that passes
through the liver every day and hour, we see that the marked
difference in the sugar content of the blood flowing to and from
the liver, while apparently small, must really indicate the pro-
duction of a very considerable amount of sugar. Seegen estimates
that in a dog of 40 kilos, weight, 400 litres of blood pass through
the liver in 24 hours, from which we must assume a production of
400 grms. sugar, supposing the blood flowing from the liver to
contain O'l per cent more sugar than the blood flowing to that
organ.
Seegen, however, raised another objection to Bernard's theory.
In 1876 he (and soon afterwards Nasse) determined the nature
of the sugar produced from glycogen by the liver, and that
formed artificially by the action of arnylolytic enzymes, and
found that the liver manufactures glucose or dextrose, while
artificial digestions of glycogen with saliva, pancreatic extract, or
succus entericus yield maltose. This fact caused Seegen to
question whether Bernard was right in assuming the intervention
of a specific enzyme in the phenomenon of glycogenesis, and
whether the glucose formed by the liver might not be derived
from some substance other than glycogen.
He accordingly undertook a series of experiments to estimate
the glycogen and glucose of the liver at different intervals after
death, to see whether as the former disappeared the latter is
manufactured in a corresponding ratio. In collaboration with
Kratschmer (1880) he obtained results unfavourable to Bernard's
hypothesis, since the quantity of sugar augments rapidly, directly
after death, while the glycogen does not perceptibly diminish,
whence he concluded that the sugar is not formed at the expense
of the glycogen.
Seegen supposed that the peptones and fats are capable of
forming the sugar of the liver, and asserted in support of his
views that fragments of liver excised from the living animal
produce a larger amount of sugar when kept for 5-6 hours at a
temperature of 38° in a solution of peptones, or defibrinated blood,
or are plunged into an emulsion of fat and gum, while a current
of air is passed through the mixture.
Seegen's results were contradicted by Delprat (1881), Chittenden
and Lambert (1885), Girard (1887), Neumeister (1890), Noel
304 PHYSIOLOGY CHAP.
Paton (1894-95), who brought forward other experimental data
agreeing with the theory that hepatic sugar is exclusively derived
from glycogen. The simplest and most direct proof of this theory
is given by Montuori (1895). He excised the liver of a newly
killed animal ; threw part into boiling water to arrest the pro-
duction of sugar, and kept another part for some time (24 hours)
at ordinary temperature, to allow the sugar to form freely. The
weight of the first and second parts of the liver was known. Both
parts were then boiled separately in a 1 per cent solution of
hydrochloric acid, so as to convert the whole of the contained
glycogen into sugar. On careful estimation of the amount of
sugar formed, he repeatedly found them to be approximately
equal in both parts of the liver. This shows that under these
conditions the glucose of the liver is formed exclusively from the
glycogen ; since if it were also formed from the proteins and
fats, more sugar would be produced in the portion of liver left to
itself for 24 hours.
Montuori's results were confirmed by E. Cavazzani in Zuntz's
laboratory. He also found that the quantity of sugar that can
be collected from the excised liver did not increase on the addition
of peptones or glycerol (after Seegen's method). Weiss (1898),
on the other hand, with Bunge, confirmed Seegen's results on
repeating the experiments with an emulsion of gum and fat.
This induced Montuori (1899) to undertake new experiments to
ascertain whether fat added to the excised liver in a suitable form
would be partially converted into sugar. His results were entirely
negative. Hesse, Abderhalden, and Eona (1904), under identical
conditions with Weiss and Seegen, did not obtain the positive
results of these authors, but confirmed the negative conclusions
of Cavazzani and Montuori. It may therefore be concluded that
there is at present no evidence that the liver when excised from
the body is able to form sugar from any material other than
glycogen.
IX. The fact that on steeping freshly excised liver from a
living animal in boiling water, the conversion of glycogen into
sugar is arrested, made Bernard refer this conversion to the work
of an enzyme, a kind of hepatic diastase. But his attempts to
isolate this enzyme, which were repeated by Hensen, led to no
conclusive results.
In 1873 Wittich succeeded in extracting a highly active
ferment from the liver (when completely bloodless, washed and
pounded) by means of alcohol.
Pavy (1894), by a method of extraction analogous to Wittich's,
confirmed his results, and isolated from the liver a specific enzyme
which determined the conversion of glycogen into glucose in vitro
with various intermediary products (dextrin, isomaltose, and
maltose).
v INTERNAL RESTITUTIVE SECRETIONS 305
These results were subsequently confirmed by Musculus, v.
Mering, Kiilz, Pregl, and others.
Theoretically the amylolytic enzyme of the liver may be
derived from a special zymogen contained in the protoplasm of the
hepatic cell, which is destroyed along with the enzyme when a
freshly excised liver is thrown into boiling water.
Noel Paton (1893) observed that chloroform or sodium fluoride
retarded the first phase of sugar- formation in the excised liver,
during the period in which it is most active owing to survival
of the hepatic cells. Since Pavy and Salkowski showred that
chloroform does not modify the activity of the amylolytic enzyme
extracted from the liver, it appears to us that the delay in
glycogenesis observed by Paton must be due to alteration of the
protoplasm of the hepatic cells. This would retard the formation
of the zymogen on which the development of diastase in the
excised liver depends.
In a recent series of experiments E. Cavazzani brings forward
the following facts : —
(a) Formation of glucose in the liver is increased by stimula-
tion of the caeliac plexus, but the amount arid activity of the
haemodiastase in the blood circulating through the liver is not
increased. Equal quantities of hepatic blood collected before and
after stimulation of the caeliac plexus convert an equal quantity
of starch into sugar in the time unit and under the same
experimental conditions.
(6) In a mixture of blood and glycogen solution the conversion
of the glycogen into sugar by the haemodiastase is very slow,
whereas post-mortem glycogenesis is a very rapid process.
(c) Methyl violet, which does not affect the saccharifying
action of haemodiastase, when injected into the circulation, be-
comes mainly fixed in the liver, and in suitable doses checks the
hyperglycaemia of asphyxia, and greatly reduces post-mortem
glycogenesis. Methyl violet (as was previously known, and
confirmed by Cavazzani) exerts a markedly paralysing action on
protoplasm.
(d~) Sulphate of quinine, again, which is indifferent to enzymes
and toxic for protoplasm, acts like methyl violet on the formation
of sugar in the liver.
Cavazzani's observations do not, however, prove that hepatic
glycogenesis is not due to an amylolytic enzyme formed by the
liver. At most they support the thesis that the diastase of the
blood does not depend on that of the liver, and that methyl violet
and salts of quinine reduce post-mortem glycogenesis because, by
paralysing the protoplasm of the hepatic cells, they obstruct the
formation of the zymogen, and its conversion into the diastatic
enzyme.
Cl. Bernard regards hepatic glycogenesis as a process of
VOL. n x
306 PHYSIOLOGY CHAP.
internal secretion. He founded this doctrine solely on the fact
that the formation of sugar in the liver is controlled by the
nervous system. In 1858 he saw that on puncturing the floor of
the rhomboidal sinus near the apex of the calamus scriptorius,
such a marked increase of sugar occurs in the blood (Jiyperglycaemia)
that it is eliminated after about an hour, by the kidneys (glycosuria}.
He also found that reflex excitation of the bulbar centre suffices
to produce the same phenomenon. In fact, stimulation of the
central end of the vagus divided between the lung and the head
will produce glycosuria. The proof that glycosuria is determined
by hyperglycaemia from excessive sugar formation in the liver
lies in the fact that diabetic puncture does not produce glycosuria
in animals in which the glycogen of the liver has disappeared (by
fasting, various intoxications, etc.).
But the importance at first attributed to the diabetic puncture
as discovered by Cl. Bernard gradually diminished, as new data
came to light. These showed that injury, destruction, or irritation
of other parts of the central and peripheral nervous system could
produce a more or less transitory glycosuria. Eckhard found
that in rabbits lesion of the vermis of the cerebellum induced
glycosuria. Schiff recognised the same phenomenon with lesions
of various parts of the brain (division of optic thalami, lesions of
cerebral or cerebellar peduncles, or of the pons Varolii, complete
section of the posterior columns of the cervico-dorsal tract of the
cord). Pavy saw that glycosuria appeared after section of the
bulb and the protracted use of artificial respiration. Lustig and
Oddi obtained glycosuria after excision of the caeliac plexus. In
our own numerous experiments on the extirpation of more or less
extensive and variously localised tracts of the brain or cerebellum,
and the total or partial section of the cord at different levels, we
have invariably, when the urine was examined, found sugar in the
first days after the operation. The same thing occurs (according
to Eckhard, Kiilz, Schiff, and others) with the stimulation or
simple section of many nerves (particularly the vagi, splanchnics,
sciatics). There is thus no circumscribed diabetogenic centre ; but it
may be said that the abnormal excitation of any important part
of the central and peripheral nervous system may directly or
indirectly provoke glycosuria.
Both Bernard and Schiff referred the phenomenon of glycosuria
consequent on nerve lesions, or the direct or reflex excitation of
parts of the nervous system, to the vasomotor disturbances, and
resulting active or passive hyperaemia of the liver. This increases
the development of hepatic diastase, and therewith the sacchari-
fication of the glycogen contained in the hepatic cells. It is also
an admissible hypothesis that the liver contains, besides the
vasomotor nerves, others which directly influence the metabolic
activity of the hepatic cells (and thus regulate the formation of
v INTEENAL EESTITUTIVE SECRETIONS 307
hepatic diastase), and that the direct or indirect excitation of these
produces the exaggerated glycogenesis and consequent glycosuria
observed as the effect of various nerve lesions.
In support of this hypothesis A. and E. Cavazzani brought
forward experimental results which appear to us of considerable
value. In 1892 they found that stimulation of the caeliac plexus
with an induced current, lasting for a few minutes, augments the
sugar content of the blood flowing from the liver. In 1894 it
occurred to them to use this means of increasing hepatic
glycogenesis, both in living and in recently killed animals, not
merely to confirm the fact that increase of sugar in the liver
coincides with a diminution of glycogen, but also to see if the
phenomenon changes in correspondence with the activity or arrest
of the circulation in the liver. They extirpated a hepatic lobe
from live and from recently killed dogs, and then stimulated the
caeliac plexus for about 15
minutes. A second lobe A B
was then excised, after
which they estimated the
glucose and glycogen in
both lobes, after weighing
and boiling them. The
results of their experiments
are briefly as follows: — In
living animals Stimulation Flo. 97._Hepatic cells of dog after fasting 36 hours
Of the Caeliac pleXUS pro- <£> j and U hours after an abundant meal (B).
,r. „ (Heidenham.) In A the cells are small and finely
duceS a marked increase OI granular; at B they are much magnified by the
1 • *-V, I;,T J accumulation of glycogen, a hyaline substance that
glUCOSe in the liver and a obscures the granulations of the cytoplasm.
comparatively greater
diminution of glycogen, because part of the sugar is carried away
as fast as it is formed by the blood current. In freshly killed
animals in which the circulation is at a standstill, the same
stimulation still produces increased glycogenesis, and the corre-
spondence between the glucose formed and the glycogen that
disappears is absolute or nearly so. From this we may conclude :
(a) that stimulation of the nerve fibres which run from the
caeliac plexus to the liver increases the hepatic glycogenesis ;
(6) that the sugar formed comes from conversion of the glycogen ;
(c) that this conversion is up to a certain point independent
of the external circulatory conditions, so that it is improbable
that the influence of the nervous system on hepatic glycogenesis
consists in a simple vasomotor action leading to increased irrigation
of the liver with blood.
E. Cavazzani further demonstrated that the glycogenesis pro-
moted by excitation of the caeliac plexus is accompanied by cyto-
logical changes in the hepatic cells, similar to those which Afanasiew
and others detected in the liver of fed and fasting animals (Fig. 97).
308 PHYSIOLOGY CHAP.
Lastly, he made important observations on the exothermal
phenomena in the liver under all experimental conditions in
which an increase of hepatic glycogenesis takes place : — (a) In
asphyxia, according to Morat and Dufour, so soon as there is hyper-
glycaemia, the temperature of the liver rises. (6) The same is
found during stimulation of the vagi when, according to Butte,
hepatic glycogenesis is exaggerated, (c) When, after cardiac
paralysis and suspension of circulation, the formation of sugar
becomes more active, while all other organs are cooling more or
less rapidly, the liver exhibits a post-mortem rise of temperature,
lasting 10-20 minutes, of half a degree or even more, (d) In
fasting or very emaciated animals the asphyxial and post-mortem
rise is almost or entirely absent, since, as we have seen, glyco-
genesis is limited by scarcity of glycogen. The opposite occurs
with well-nourished animals, (e) In animals into which curari
or atropine, or methyl violet in suitable doses, is injected intra-
venously, neither asphyxial hyperthermia nor hyperglycaemia is
perceptible. With injection of methyl violet, post-mortem glyco-
genesis is also suspended, in correspondence with which fact the
temperature of the liver falls rapidly like that of the other organs.
From these facts, as a whole, it is evident that the hepatic
glycogenesis by which glucose is formed from the glycogen and
poured into the blood, is accompanied by phenomena highly
similar to those observed during the secretion of other glandular
organs.
X. It now remains to see from what constituents the glycogen
which serves for the secretion of glucose originates, and whether
other tissues besides the liver are capable of forming or storing up
glycogen as a reserve material.
In the first place, it must be observed that the amount o:
glycogen accumulated in the liver varies considerably with
different animals, and also in the same animal under ' different
conditions of nutrition and diet. Pavy, in dogs which had been
fed for a long time on bread and potato, found 15 per cent
glycogen in the liver. In rabbits fed on starchy foods and
beetroot it amounted to a maximum of 27 per cent. Supposing
the human liver to be capable of accumulating 10 per cent of
glycogen, and the weight of the liver to be 1500 grms., we should
have 150 grms. glycogen stored up in this organ.
That the glycogen content of the liver depends essentially on
diet has been convincingly proved by the fact that during an
absolute fast the glycogen wholly or almost entirely disappears
from the liver, in rabbits after 5 days, in dogs after 2-3 weeks.
According to Pfliiger, the glycogen never disappears completely,
even in rabbits ; in dogs a certain amount remains even after a
fast protracted for weeks.
When an animal that has been almost entirely deprived of its
I
t
v INTERNAL EESTITUTIVE SECEETIONS 309
hepatic glycogen by fasting is fed on a diet rich in carbohydrates,
the glycogen of the liver is rapidly formed again, and may be
present in a considerable quantity a few hours after the meal.
It is certain that the chief part of the hepatic glycogen is
derived from the alimentary carbohydrates. Voit saw that the
readily fermentable monosaccharides, both dextrose and laevulose,
are converted into glycogen in the liver, either when introduced into
the intestine of a rabbit that has fasted for 4 days (and is thus
almost destitute of glycogen), or when injected directly but slowly
into the circulation. The disaccharides, saccharose and maltose,
which ferment less readily, only form glycogen when they are
introduced into the intestine, where they are converted into
monosaccharides previous to absorption.
The sugar absorbed from the intestine, carried to the liver, and
there converted into glycogen by a process of dehydration and
cleavage, prevents hyperglycaemia, or the abnormal increase of
blood-sugar which produces glycosuria, i.e. its useless elimination
by the kidneys. Pavy noted (1867-69) that slow injection of
sugar by one of the veins leading to the portal does not produce
glycosuria ; while sugar injected with the same precautions and in
the same dose into the jugular vein is partially excreted with the
urine. This fact, subsequently confirmed by others, shows that
sugar when it goes direct to the liver becomes fixed there in the
form of glycogen as a reserve material. Luchsinger (1875) gave
direct evidence of this, when he succeeded in increasing the
amount of glycogen in a liver recently excised from the body, by
irrigating it artificially with blood containing 2 per cent glucose.
When the amount of sugar introduced with the food is
excessive, the liver is no longer able to fix and store it all up in
the form of glycogen, so that a certain quantity passes through,
and is eliminated by the kidneys (alimentary glycosuria). Accord-
ing to Hofmeister, the limit of assimilation of glucose oscillates in
the dog between 0'5 and 2 grrns. for each kilo, body- weight; the limit
for saccharose is higher, for lactose lower. For man, according to
von Noorden, the limit of assimilation for cane sugar is on an
average 200-250 grammes. Unlike sugars, starchy substances
never, under normal conditions, produce alimentary glycosuria,
either in man or animals, probably because they undergo com-
paratively slow digestion in the intestine, so that absorption of
the sugar formed, and its passage into the blood, are delayed and
take place very gradually.
Not the whole of the sugar absorbed by the intestine after a
diet rich in carbohydrates can be fixed and stored up in the liver.
This is evident if we consider the comparatively scanty quantity
of glycogen contained in the liver, and reflect that previous to
each meal the liver already contains a good store of glycogen,
which does not entirely disappear even after several days of fasting.
x i
310 PHYSIOLOGY CHAP.
It is therefore necessary to admit that other organs besides
the liver are capable of fixing the sugar in the form of glycogen,
since we know that an excess of absorbed sugar cannot circu-
late in the blood without being eliminated by the kidneys. We
know in fact that almost every animal organ contains small quan-
tities of glycogen ; particularly so the muscles, as first shown by
Bernard for the muscles of the foetus (1859), and later by Xasse
(1869) for the muscles of the adult. The percentage glycogen
content of adult muscle is much lower than that of the liver, and
seems to vary considerably not only in different animals, but also
in different muscles of the same animal. According to E. Voit
the glycogen content of the whole of the muscles is slightly in
excess of that stored up in the liver. In muscular work, by
analogy with what occurs in fasting, the glycogen is consumed
until it entirely disappears, not merely from the liver but from
the muscles also. According to Kiilz and Aldehoff the glycogen
of the liver disappears more rapidly than that of the muscles, as if
the liver supplied it to the muscles in proportion as they use it up.
In muscles paralysed by section of the nerves that supply them,
increase of glycogen has been found accumulated in consequence
of the muscular immobility. In experimental strychnine tetanus,
on the other hand, the glycogen can be made to disappear from
the muscles and also from the liver. When the muscles enter into
rigor mortis the glycogen is converted into glucose and lactic acid.
All embryonic tissues, as Bernard already recognised, contain
a considerable amount of glycogen (particularly the muscles and
the placenta), so long as the liver is little developed, and contains
only traces of glycogen. Later on the muscles gradually lose their
glycogen, while the liver accumulates more and more of it.
It is not certain that the glycogen of the muscles is identical
with that of the liver. Hepatic glycogen is certainly conveyed to
the muscles in the form of glucose, since Kiilz demonstrated that
the muscles also are capable of fixing the sugar and converting it
into glycogen. In fact, the glycogen content of the muscles can
be increased in a frog deprived of its liver, by subcutaneous injec-
tion of sugar. On the other hand, the presence of glycogen in
the blood plasma has not been demonstrated, and where traces are
found, these are due to the disintegrated leucocytes which, like
other tissue-cells, contain glycogen (Frerichs).
The glycogen of the liver, as also of the muscles, is rapidly
consumed when the animal is made to develop much heat to keep
its temperature constant. If a rabbit be cooled in a cold bath, or
kept in an atmosphere below zero, all the glycogen accumulated
in the liver disappears (Kiilz). The same occurs with white rats
(Zatsch). Cold-blooded animals exhibit the opposite phenomenon.
If the temperature is raised, their glycogen disappears, owing to
accelerated metabolism. When a hibernating frog, whose cells
v INTEENAL EESTITUTIVE SECEETIONS 311
are surcharged with glycogen, is brought into an atmosphere of
20° C. or more, the glycogen entirely disappears after a certain
time (Foster).
From all these facts we see that (a) glycogen arises principally
from the carbohydrates of the food; (&) it is formed (by a
synthetic regeneration and dehydration) from the sugar absorbed
by the intestine, not merely from the liver, but also from the
muscles and other tissues ; (c) it functions as a reserve material,
in analogy with vegetable starch, which plant tissues use as a
source of energy.
XL Although the larger part of the glycogen stored in the
tissues of the body comes from the carbohydrates of the food
(owing to a synthetic chemical process due to the anabolic activity
of living cells in general, but particularly those of the liver and
of striated and plain muscle), it is certain that part at least of
the glycogen and glucose normally found in the body are formed
by an analytic chemical process from the proteins, and also by
decomposition of the fats — a process effected by the katabolic
activity of the tissues.
Cl. Bernard always insisted that part of the hepatic glycogen
came from the alimentary proteins, in view of the constant
presence of glycogen in the liver of dogs fed for a long time on an
exclusively flesh diet. This argument does not, however, settle
the question, since the muscles (as we have seen) always contain
a certain amount of glycogen or the sugar formed from it. But
protracted experiments with a diet of pure proteins, — albumin,
fibrin, caseinogen, — according to v. Mering, Kiilz and others, do
cause the reappearance of glycogen, although in small quantities,
in animals deprived of it by fasting.
The experimental evidence which Seegen and Weiss brought
forward in support of this theory (p. 303) was contradicted by
other workers (Montuori, E. Cavazzani, Hesse, Abderhalden).
Pfliiger is among those who deny that glycogen is partly
formed from alimentary protein. In his classical monograph
Glycogen (1905) he reviews all his experiments on various animals
kept fasting for a longer or shorter time, and then fed up again
either with meat, or with special proteins destitute of glycogen
and glucoprotein.
He demonstrates that the percentage of glycogen found in
the animals experimented on, came within the limits of that
in the fasting control-animals, plus that amount of glycogen due
to the carbohydrate present in the flesh diet. So that if, after
feeding-up again, glycogen appears in excess of that in the fasting
control, this does not, according to Pfliiger, prove it to be formed
from the alimentary protein. The latter may stimulate the
production of glycogen by utilising . the fat, without actually
participating in such production. According to Pfliiger, this
X2
312 PHYSIOLOGY CHAP.
theory is substantiated by the fact that on feeding urea mixed
with alimentary protein, the formation of glycogen increases,
although the urea is eliminated again, and cannot play any part
in the formation of the glycogen. His argument does not,
however, carry conviction, because he gives no direct proof of his
thesis.
Other undeniable facts can be mustered in support of
Seegen's position. Voit noticed that even after 80 days' torpor
the liver of the marmot contains a large amount of glycogen,
which can, he says, only be explained on the assumption that the'
liver during hibernation goes on forming glycogen at the expense
of the proteins which the animal has at its disposal. Kiilz,
however, denies this interpretation, and maintains that the
glycogen found by Voit is the residue of that formed in previous
feeding, the consumption of which is arrested during hibernation.
He killed four marmots at different intervals after the commence-
ment of torpor, and found approximately the same amount of
glycogen in the liver. In our opinion this fact does not, however,
preclude the possibility that glycogen is slowly formed during
hibernation, in quantities approximately equal to what is simul-
taneously consumed. The argument of Klilz may be met by
another apparently enigmatical fact, which Aducco noticed in
1889 on pigeons that were kept in the dark and starved. The
glycogen regularly disappeared from the liver in the first days of
fasting, but reappeared in the succeeding days in considerable
amount. There seems but one rational interpretation of this
phenomenon. In the first days of inanition, when tissue meta-
bolism is still fairly active, the amount of glycogen consumed
much exceeds that simultaneously formed, so that the reserve of
this material is entirely exhausted. In the subsequent days of
starvation, on the other hand, when general metabolism is greatly
retarded, the quantity of glycogen formed is greater than that
simultaneously consumed, so that a new store accumulates in
the liver.
By an identical process the hepatic cells of the frog accumulate
a large amount of glycogen during the winter, while in summer,
when metabolism is very active, they contain hardly any, since
it is consumed as fast as it is formed (Langley). As the intensity
of general metabolism in the frog (and in cold-blooded animals
generally) depends on the external temperature, it is easy to
reduce or entirely abolish the glycogen accumulated in the liver
of a hibernating frog, by exposing it for some time to a temperature
of 20-22° C. Conversely, it is possible to obtain a certain amount
of glycogen from the liver of a summer frog after exposing it for
several days (Fig. 98) to a very low temperature.
It is evident that the accumulation of glycogen in the hepatic
cells during natural or artificial torpor does not depend on
INTERNAL RESTITUTIVE SECRETIONS
313
alimentation, since the hibernating frog entirely abstains from
food. Under these conditions, therefore, the glycogen cannot be
formed at the expense of the carbohydrates ; in all probability it
is formed by cleavage of the protein molecule, on which the carbo-
hydrate groups are liberated from the nitrogenous groups.
It is, further, not impossible that under these or similar
conditions, in which glycogen and sugar are formed independent
of the alimentary carbohydrates, part at least of these products
may arise from cleavage of the fat molecule with absorption of
'oxygen. According to Bunge, this hypothesis is supported by the
fact that the blood of animals in protracted inanition (when the
glycogen store is exhausted) always contains a small and almost
A.
constant quantity of sugar, and that under these conditions the
consumption of nitrogenous substances is minimal, while the fat
reserves are being rapidly exhausted.
In support of the possible derivation of sugar from, fat, Bunge
brings forward the argument that this origin has long been
familiar in plant physiology. In 1859 Sachs demonstrated that
the fat disappears from oily seeds set in the dark to germinate,
in proportion as starch, gum, sugar, and cellulose were formed.
Wiesner further demonstrated that absorption of oxygen accom-
panies and is a necessary condition of this conversion of fat into
carbohydrates.
Chauveau adduced the following evidence to the same effect : —
(a) injection of glycerol into the intestine causes increase of
hepatic glycogen, as demonstrated by van Ueen. (&) During the
metamorphosis of the chrysalis of Bombyx mori, fat diminishes
314 PHYSIOLOGY CHAP.
while glycogen increases. (c) During hibernation the fat of
marmots disappears gradually, while the glycogen, as we have
seen, remains almost constant.
The possibility of the formation of sugar from glycerol was
chemically demonstrated by Ernil Fischer. Cremer and A.
Liithje further observed that when glycerol was administered to
depancreatised dogs, glycosuria increased approximately in pro-
portion to the dose. They concluded that a similar conversion
took place within the body.
Other cogent arguments in favour of the theory which derives
a part of the sugar normally formed in the body from the
decomposition of proteins or of fat can be adduced from the well-
known disease of diabetes mellitus, the chief symptom of which is
the constant presence of a large amount of sugar in the urine,
identical with that formed in the liver from the glycogen (glucose
or dextrose}. In its milder forms, the diabetes ceases with the
absolute exclusion of carbohydrate from the diet ; in the graver
forms, the sugar is decreased, but does not entirely disappear from
the urine, even with an exclusively flesh diet. Innumerable
investigations have been devoted to the study of this disease, and
if all that has been published on the subject were collected it
would, as Bunge remarked, furnish a library.
Our task is to define the fundamental points of this complicated
problem. Does diabetes depend on an alteration of the kidneys,
by which the epithelia of the urinary canal allow the glucose
constantly present in the blood to filter through more readily?
No ; for diabetes is constantly associated with hyperglycaemia, i.e.
increase of sugar in the blood, rising from 0'05-0'15 per cent to
0'22-0'44 per cent. Does it depend on increased hepatic glyco-
genesis ? No ; because the liver of persons who have died of diabetes
show in not a few cases a definite, sometimes a considerable, amount
of glycogen in the liver (Kiilz, v. Mering), although as a rule it
contains but little, as shown by Fig. 99, which gives the iodine
reaction of the liver cells of a normal person and of one who has
died of diabetes. Glycogen has, moreover, been found in the
hepatic cells extracted during life in severe diabetes, by puncture
of the liver with a trocar (Frerichs). On the other hand, it is
interesting to note in diffuse diseases of the liver (hepatic
cirrhosis, acute fatty degeneration, phosphorus poisoning) that
there is no sugar in the urine, since both glycogen and sugar
have entirely disappeared from the liver. In 17 cases of phosphorus
poisoning Frerichs found no trace of sugar in the urine ; after
administration of 100-200 grms. glucose he only saw it appear in
minute amounts in two cases. It is thus impossible to account
for diabetes on the assumption that the hepatic cells have become
less able to store up sugar.
All the evidence makes it probable that the hyperglycaemia
INTERNAL RESTITUTIVE SECRETIONS
315
and glycosuria which represent the main symptoms of diabetes
depend on a lowered glycolysis, i.e. on the fact that the diabetic
organism does not possess the normal capacity for splitting up the
sugar as it is formed. This capacity is not entirely lost, but it is
much diminished. Kiilz, indeed, noted that in severe cases of
diabetes the amount of sugar in the urine is always lower than
the total of carbohydrates ingested, and absorbed from the intestine
in the form of sugar.
Another very important observation of Klilz is that diabetics
are capable of breaking up laevulose or fruit sugar, which turns
FIG. 99.— Hepatic cells of man under normal conditions (A), and in a diabetic subject (B) treated
with gum iodide. (Frerichs.) At A the colour is strongly reddish-brown from the glycogen
present ; at B the colour is pale, from small amount of glycogen,
the plane of polarised light to the left. They can also use inulin,
which is converted into laevulose as starch is converted into
dextrose. Lastly, he observed that saccharose (which splits half
into laevulose and half into dextrose), when given in severe cases
of diabetes, increased the sugar in the urine by about half the
amount of sugar (in the form of dextrose) administered as
saccharose. The repetition of this experiment by several other
observers yielded results which were not always in agreement
with those of Kiilz. This proves that different diabetics behave
differently. Generally speaking, however, the ingested laevulose
either does not appear or appears only in very small quantities in
the urine. Sometimes part of the laevulose is converted into
dextrose, and appears as such in the urine. On the strength of
316 PHYSIOLOGY CHAP.
these data we may conclude that diabetics have to a large extent
lost the power of utilising dextrose and glucose.
Since the greater part of the sugar formed in the body is
consumed by the muscles, which function under the influence of
the nervous system, it is natural to conjecture that the patho-
genesis of diabetes is to be found in a specific alteration of the
nervous system, more or less diffused in the centres.
Bernard's so-called diabetic puncture, of which we have already
spoken, seemed at first sight to clear up the obscure pathogenesis
of diabetes mellitus. But the glycosuria due to puncture of the
fourth ventricle is quite transitory ; it ceases after a few hours,
and the liver remains almost free of glycogen. Puncture does not
produce glycosuria in an animal deprived of its glycogen by fasting.
If glucose be injected into the mesenteric vein of an animal in
which the glycogen store in the liver has been exhausted by
fasting, but little sugar escapes with the urine, viz. only that
which the liver is unable to fix in the form of glycogen. If, on
the contrary, the glucose be injected into the mesenteric vein of
an animal that has suffered Bernard's puncture, almost the whole
of the sugar is eliminated by the kidneys (Naunyn). It is there-
fore clear that Bernard's so-called experimental diabetes is a process
fundamentally distinct from the true diabetes mellitus, which, as
we have seen, does not depend on incapacity of the liver to form
or to retain glycogen.
Another form of temporary glycosuria is that which v. Mering
obtained in 1886 by means of phloridzin. This glucoside (\vhich
is extracted from the root-bark of apple and cherry trees) on
boiling with acid breaks up into phloretin and dextrose. When
introduced into the stomach of dogs in a quantity of 1 grm. per
kilo, body-weight, a glycosuria lasting 2-3 days is produced after
a few hours. If the animal be killed after glycosuria has ceased,
the glycogen accumulated in both the liver and the muscles is
found to have entirely disappeared. So far the process seems to
be identical with that which ensues on Bernard's puncture : but
it differs essentially in that a second dose of phloridzin administered
to the animal after the effect of the first has worn off, regularly
reproduces the glycosuria. It is evident that the sugar produced
and eliminated after this second poisoning cannot originate in
dextrose formed by phloridzin decomposition nor from glycogen,
which no longer exists, but that it must come from other materials
present in the body, possibly from either the proteins or the fats.
The action of the liver does not seem to be necessary to the
production of phloridzin diabetes. It can in fact be produced in
the frog after removal of the liver.
Minkowski maintains the hypothesis of the renal origin of
phloridzin diabetes, and assumes that the drug breaks up in the
kidneys into phloretin and glucose ; that the latter is eliminated,
v INTERNAL KESTITUTIVE SECRETIONS 317
while the phloretin unites once more with the circulating glucose,
the new phloridzin being again decomposed in its passage through
the renal tubules.
Other intoxications are capable of producing glycosuria or
transitory diabetes, e.g. poisoning with curare, with a strong dose
of morphine, with amyl nitrite, carbon monoxide, and many other
poisons. These analogies and the differences between the various
processes which give rise to common symptoms of glycosuria have
not been sufficiently investigated.
Another form of experimental diabetes presents a more striking
analogy with spontaneous diabetes; this was first discovered by
De Dominicis in Italy (1889), and simultaneously by v. Mering
and Minkowski in Germany. When the pancreas is entirely
removed in a dog (as also in other animals of different classes of
vertebrates), all collateral lesions being as far as possible avoided,
so that the animal is able to survive this grave operation, a severe
form of diabetes invariably sets in with all the characteristic
symptoms of spontaneous diabetes — abnormal hunger and thirst,
polyuria, depression of muscular energy, etc. The elimination of
sugar does not usually begin immediately after the operation, but
in 4 to 6 hours, or even later, usually on the second day. It
rapidly increases in intensity, and reaches its maximum 24 to 48
hours after the operation with about 8 to 10 per cent of sugar in
the urine. If food is cut off, the elimination of sugar decreases,
but does not absolutely disappear till after 7 days' absolute fast.
With abundant food, the sugar eliminated by the kidneys may
amount to 10 to 12 per cent, and even more. With an exclusively
flesh diet, a dog of 15 kgrms. may excrete 102 grms. sugar per
diem. If bread be added to the meat, the absolute quantity of
sugar eliminated may be even greater, e.g. a dog of 8 kgrms.
excreted 70 to 80 grms. daily for a considerable period. As in
spontaneous diabetes, considerable quantities of acetone, acetic
acid, and oxybutyric acid are given off with the sugar. As in
spontaneous diabetes, there is conspicuous hyperglycaemia, e.g. in a
dog operated on six days previously there was 0'3 per cent, in
another, 27 days after operation, 0'46 per cent sugar in the blood.
The glycogen almost entirely disappears from the liver and muscles
after the operation ; but these organs do not lose their power of
forming it by synthesis, and also of accumulating it to some extent.
In fact new glycogen can be found in both liver and muscles, after
feeding with laevulose, which, as in spontaneous diabetes, can be
utilised and only partially escapes into the urine, and that after its
conversion into dextrose. Dextrose, however, if administered as a
food, reappears entirely in the urine. These facts have been gener-
ally confirmed by many observers, both in Italy and elsewhere.
Glycosuria has rarely been found absent after complete extirpation
of the pancreas (Cavazzani and others); sometimes after total
318 PHYSIOLOGY CHAP.
excision intermittent instead of persistent glycosuria has been
observed (Paderi); sometimes severe glycosuria occurs even with
partial excision (Sandmeyer).
Many and various have been the hypotheses put forward to
explain the relation between loss of pancreas and diabetes. Some
of these can at once be set aside, on the strength of experimental
data.
As we saw in considering the internal function of the pancreas
(see pp. 98-102), the genesis of pancreatic diabetes was at first
explained by the serious disorder of the intestinal processes that
occur after loss of the digestive functions of the pancreatic enzymes.
De Dominicis ascribed the pancreatic diabetes to an auto-intoxica-
tion due to the absorption of abnormal substances developed in the
intestine, after suppression of the various functions of the pan-
creatic juice. Gaglio, in support of this notion, added that the
toxin which causes the diabetes penetrated from the intestine to
the blood, by the lymphatics.
This hypothesis was, however, contradicted by the fact that a
segment of pancreas isolated from the intestine and from the
abdominal cavity (Minkowski, Hedon, U. Lombroso), or excreting
outside the body (Minkowski, Burkhardt, U. Lombroso), sufficed
to check the development of diabetes. It is thus necessary to
admit that the pancreas, besides its office of secreting digestive
juice, is the seat of an internal function, by which the formation
or consumption of glucose is regulated (see pp. 98-102).
Others suppose that a toxic substance capable of producing
diabetes is continually formed in the body, and is normally
destroyed by the pancreas as fast as it is formed. After removal
of the pancreas, diabetes would develop by a kind of auto-intoxica-
tion, analogous to that which occurs after thyroidectomy. But
this hypothesis has been experimentally proved fallacious. It was
demonstrated first by von Mering and Minkowski, and subsequently
by He'don, that intravenous injection of blood from a diabetic dog
neither produces glycosuria in a normal animal, nor increases it if
present after loss of the pancreas.
A. and E. Cavazzani, who, as we have seen, discovered nerve
fibres to the liver in the caeliac plexus, which, on excitation, pro-
mote hepatic glycogenesis, suggested that the diabetes consequent
on excision of the pancreas is due to the operative act in which
these nerves, which regulate the production of glucose in the liver,
are injured. In fact, they described lesions both of certain cells in
the caeliac plexus and of the hepatic cells in depancreatised animals.
They were thus led to assume an analogy between pancreatic
diabetes and Bernard's paralytic secretion of saliva, taking both to
be the effect of a degenerative irritation of the secretory nerves.
Several data, however, tell against this hypothesis. It is possible
to excise a large part of the pancreas without inducing true
v INTERNAL EESTITUTIVE SECRETIONS 319
diabetes, which is only seen when the organ is completely removed.
On the other hand (see p. 99), the whole of the solar plexus can
be excised without producing permanent diabetes, transitory glyco-
suria with acetonuria only being manifested.
According to Lepine and his pupils, pancreatic diabetes depends
on the absence from the blood of a glycolytic ferment of pancreatic
origin, which normally oxidises the circulating sugar (see Vol. I.
p. 127). According to 0. Cohnheim, again, this ferment of
pancreatic origin acts normally not only on the blood, but also
on the various tissues of the body. Pniiger contests both these
opinions. As against Lupine he points out that researches in vitro
show too small a decrease in the sugar content of the blood
(4 to 6 per cent) in one hour, to explain the combustion of the
carbohydrates. This objection does not, however, meet Cohn-
heim's position. If we take into consideration the combustion not
only of the blood-sugar but that of all the sugar contained in the
body, the combustion of 6 per cent in one hour would, under
normal conditions, account for the total combustion of sugar in the
course of the day. Further research is needed to clear up this
important question.
Montuori asserted the importance of the liver in the genesis of
pancreatic diabetes (1895). He found by ingenious experiments
that when pancreatic extract was added by various means to
excised liver, less sugar was found after some time than in other
portions of the same liver not submitted to similar treatment.
According to him this depends, not on the glycolytic action of a
specific enzyme, as assumed by Lepine and Sympson for the pan-
creas, but on an inhibitory action on hepatic glycogenesis by the
pancreas, as was also held by Kaufmann. But in addition to certain
theoretical objections, which might be made against the view of
Montuori, his experimental results are contradicted by numerous
experiments of Pariset (1904-5).
Marcuse found a proof of the importance of the liver to
pancreatic diabetes, in the fact that while diabetes always appears
in the depancreatised frog (as shown by Aldehoff) it does not occur
in frogs deprived of both pancreas and liver. Montuori experi-
mented to see if the same result could be obtained in dogs also.
Instead of excising the pancreas he tied all its veins, and instead
of excising the liver he tied the portal vein and hepatic artery
simultaneously; instead of examining the sugar content of the
urine after these successive operations, he estimated the sugar
content of the carotid blood. Half an hour after ligation of the
pancreatic veins he found a marked augmentation of the percent-
age of sugar in the blood; about an hour after ligation of the
portal and the hepatic artery he found a diminution in the sugar
of the blood, which sometimes fell below normal. Montuori
correctly interpreted these results as showing that when the
320 PHYSIOLOGY CHAP.
hepatic circulation was cut out, the principal source of sugar in
the blood was wanting ; the sugar was locked up in the liver, and
the hyperglycaemia and diabetes consequent on the lost inhibitory
actionjof the pancreas on sugar production WQre not developed.
To explain the hyperglycaemia consequent on removal of the
pancreas, another hypothesis was invoked, to the effect that the
sugar formed in the body undergoes, in passing through the
pancreas in the blood, a conversion which facilitates its consump-
tion. This theory, however, seems improbable, when we reflect
(a) that only a small amount of the total mass of the blood
traverses the pancreas : (6) that a tenth part of the pancreas left
in situ is sufficient to impede the production of glycosuria ; (c)
that (according to observations of Capparelli) in cases in wThich
fragments of pancreas are left adhering to the mesentery, or free
in the abdominal cavity, glycosuria is delayed, and appears only
when these fragments are destroyed by necrotic processes ; (d) that
the glycosuria consequent on complete excision of the pancreas
(also according to Capparelli) is temporarily suspended when
extremely fresh pancreatic juice or pulp from the pancreas of an
animal recently killed during digestion, and diluted with physio-
logical saline, is injected into the abdominal cavity ; (e) that, lastly,
the content of glucose does not differ perceptibly (according to
Pal's work in Strieker's laboratory) in the blood flowing to and
from the pancreas.
All these facts, on the other hand, agree with the hypothesis
of an internal secretion of the pancreas, a hypothesis admitted
to-day by almost all who have occupied themselves with this
difficult subject (see pp. 98-102).
The next point is to determine the nature and mode of
action of this internal secretion of the pancreas. Does it exert
an inhibitor!/ action on glycogenesis, as believed by Montuori,
or a glycolytic action, as many others hold ? The data invoked
in aid of the first opinion appear to us to be uncertain. On
the other hand, facts are not wanting which speak decisively
in favour of the second hypothesis. Among the latter must be
emphasised the important phenomenon observed by Colasanti
and Bonanni (1897) in their investigation of metabolism in
two dogs before and after removal of the pancreas. They saw
that the carbonic acid excreted by these animals after complete
ablation of the pancreas was less by ^-f than that excreted
normally, i.e. before the operation. While under normal conditions
dog A eliminated 640 c.c. carbonic acid, and dog B 636 c.c.
carbonic acid, per hour and per kilo, body- weight ; after de-
pancreatisation, under the same conditions, the first eliminated
494 c.c., the second 230 c.c. The difference is a loss of -£~f . This
result, which agrees with the observations of Schmidt, Livierato,
Boecker and Bartels, on diabetics, can only be due to a diminished
v INTERNAL RESTITUTIVE SECEETIONS 321
consumption of the sugar which forms the principal source of
carbonic acid production. The glycolytic processes are thus
considerably reduced in intensity in pancreatic diabetes.
Pfliiger, in his important monograph on Glycogen (1902-3),
maintained the exact opposite, and held that the hyperglycaemia
and glycosuria consequent on ablation of the pancreas depend not
on decreased glycolysis but on increased glycogenesis, in excess of
the limits within which the body is able to burn up the sugar
introduced into it, or which it forms.
How this hyperglycogenesis takes place in depancreatised
animals is not very clear from Pfliiger's many publications on the
subject. For a long time he maintained that the amount of
sugar present in the urine of depancreatised dogs is never in excess
of that furnished by the glycogen stored up in the body, and
derived from alimentary carbohydrates. But after fresh experi-
ments undertaken in a controversy with Liithje, he convinced
himself of the necessity of admitting that glucose may arise from
other sources, particularly from the fats accumulated in the liver,
while on the other hand he excluded the alimentary proteins, for
which Liithje argued. Gerhardt had observed that much fat could be
extracted from the blood and liver of the dog during pancreatic
diabetes ; Pfliiger, after 16 days' pancreatic diabetes in a fasting
dog, observed an increase of weight in the liver owing to an
enormous amount of fat. It is thus probable, according to Pfliiger,
that in pancreatic diabetes the fat co-operates in sugar formation
to an amount so much in excess of that normally formed as to
produce elimination of the excess by the kidneys.
In 1903, to explain the hyperglycogenesis in pancreatic diabetes,
Pfliiger invoked the existence in the pancreas of an anti-diastase
which normally moderates the action of the diastases of the liver
cells; in ablation of the pancreas the increase in glycogenesis
would result from the deficiency of an ti- diastase. In 1905, on
the contrary, he supported the theory of the nervous origin of
pancreatic diabetes, which he regards as a nerve reflex.
In order to demonstrate that the oxidative processes are not
diminished in diabetics, Pfliiger cites the observations of certain
authors, according to which the elimination of C02 in diabetics is
equal to the amount normally eliminated (contrary to the positive
results of Colasanti and Bonanni on depancreatised dogs). This
argument does not, however, seem to us conclusive. The normal
animal is capable of burning up an enormous amount of alimentary
carbohydrate before glycosuria from insufficient glycolysis makes
its appearance. Depancreatised animals, on the contrary, do not
cease to eliminate sugar even during a prolonged fast until they
die from starvation. Obviously, therefore, the contention that
pancreatic diabetes is due to increased glycogenesis rather than to
decreased glycolysis has no value. Increased glycogenesis can only
VOL. II Y
322 PHYSIOLOGY CHAP.
be invoked in such transitory forms of glycosuria as are observed
in experimental nerve lesions (Bernard's puncture, ablation of
caeliac plexus, extirpations or lesions of different segments of the
central nervous system, etc.). In all these cases there is a rapid
glycogenesis of the glycogen of the liver, and in the absence of
glycogen, glycosuria (as we have seen) does not make its appearance.
This shows the possibility of its being due to the sudden hyper-
glycaemia induced by the entry into the circulation of the glucose
stored in the liver in the form of glycogen.
The final conclusion which stands out from the mass of facts
we have been reviewing is that in pancreatic diabetes glycolytic
processes are reduced, although glycogenic processes are not
augmented.
While not a few important questions remain wholly unsolved,
it is undeniable that experimental investigation of pancreatic
diabetes has thrown much light on the pathogenesis of spontaneous
diabetes, in which a more or less evident alteration of the
pancreatic parenchyma has been detected in all recent researches.
XII. The Fats, absorbed in the form of soaps, regenerated by
the synthetic activity of the intestinal epithelia, and broken up
into minute droplets in passing through the walls of the central
lacteal of the villi, are (as we have seen) poured out by the thoracic
duct into the blood torrent, where they give a more or less milky
aspect to the blood plasma according as the diet has been more or
less rich in fats.
After a short time, however, the fat content of the blood,
which may immediately after absorption amount to 1 per cent of
the total mass of the blood (and even exceed it, up to a maximum
of 6 per cent according to Bleibtreu) becomes much diminished,
till shortly before a meal, and in a prolonged fast, traces only of
fat are left in the blood plasma (Vol. I. p. 130). When but
little fat is given with the food, it is evidently consumed during
the day, perhaps within the blood, either by direct oxidation, or in
consequence of the katabolic activity of the leucocytes of the blood
and lymph. These always contain a certain amount of fat globules
ingested by the phagocytes, which can be distinguished from the
protoplasmatic granules by the fact that they discolour in ether
and stain black with osmic acid. After a plentiful meal of fat,
however, the fat escapes to a great extent from the blood, and is
stored up in the tissues as a reserve material, as we found to be
the case with the carbohydrates.
We are wholly ignorant of the mechanism by which the fats
leave the blood, and penetrate to the interior of the tissue cells.
Since fat must be decomposed and saponified before it can be
absorbed by the epithelium of the intestine, it is probable, according
to Altmann, that cleavage is again required before it can leave
the blood and penetrate into the tissues, which must be followed
v INTERNAL EESTITUTIVE SECRETIONS 323
by a further synthetic reconstruction within the cytoplasm.
However this may be, it is certain that fat almost entirely dis-
appears from the blood plasma, and passes into the areolar con-
nective tissue (probably by means of the leucocytes), where it is
incorporated and stored up in the connective tissue corpuscles to
be utilised as the body requires it.
The first experimental demonstration of this fact was given by
Fr. Hofmann (1872). He caused the whole of the fat to disappear
from a dog by a thirty days' fast. As the index of the complete
consumption of fat, he took the rapid increase of nitrogen in the
urine which immediately precedes death from inanition. When
this occurred, he began to feed the dog with much fat and little
meat, of which he estimated the exact protein and fat content.
After five days he killed the animal, and estimated the total
amount of fat present in the whole body, exclusive of that left
in the intestine. He found that in five days the animal had
accumulated 1353 grms. fat. Since it was impossible that the
whole of this fat should be derived from the few proteins ingested
(which would have yielded a total of 131 grms. fat), the alimentary
fat must be assumed to have accumulated in the tissues.
Pettenkofer and Voit (1873) took another way of demonstrating
the same fact. They determined the total intake and output of
dogs fed copiously with fat and scantily with meat. They saw
that the whole of the nitrogen introduced was excreted with the
urine and faeces, while a large amount of the ingested carbon was
retained in the body. Thus the organism had accumulated a
large amount of a non-nitrogenous substance rich in carbon, which
substance could only be/at.
Many tissues besides the adipose connective tissue are able to
accumulate fat. After a meal rich in fats, fat-globules of various
sizes are seen in the plain and striated muscle fibres, in the nerve
cells, gland cells, and especially in the hepatic cells. The chief
storehouse of fat is certainly the adipose connective tissue which
forms the panniculus adiposus beneath the skin, and covers or
fills the spaces in many internal organs, in a variable amount and
form adapted to the different localities. It should be noted that
adipose tissue is more variable in volume than any of the other
tissues, that it increases or diminishes in a comparatively short
time, according as the individual takes an excess or insufficient
amount of food. The fattening of stock is due principally to
abundant diet, and to limited muscular work.
In examining a lobule of subcutaneous adipose tissue, under
the microscope, with a low power, it appears (as shown in Fig. 100)
to be a collection of round globules which are highly refractive
and crowded together. These stain black with osmic acid, and
consist of irregular lobules, united by a scanty amount of fibrillar
connective tissue, which follows the course of the blood-vessels.
324
CHAP.
On examining a portion of a fatty lobule with the high power
(Fig. 101), the fat globules are seen to be enclosed within round or
FIG. 100. — Small lobule of fat from the subcutaneous tissue of guinea-pig. (Schafer.) Magnified
about 20 diameters, a, small artery to lobule ; v, small vein. The capillaries within the
lobules are not visible.
oval bladders of different sizes (80-40 /*) which are the residuum
of the original protoplasm of the connective tissue cells, the nuclei
of these being still present, though often hard to see, since they are
FIG. 101.— A few cells from the margin of the fat-lobule represented by the preceding figure.
(Schafer.) Highly magnified, f.g, fat-globule distending fat-cell ; n, nucleus ; m, membranous
envelope of fat-cell ; c r, bunch of crystals within a fat-cell ; c, capillary vessel ; v, venule ;
c.t, connective tissue-cell ; the fibres of the connective tissue are not represented.
displaced and compressed by the fat-drops which distend the
bladder. The fat-cell is thus only a connective tissue corpuscle
reduced by the accumulation of fat in its cytoplasm to a vesicle
325
surrounding the fat, which is a little denser at the point where
the displaced nucleus lies. After the fat has been removed by a
proper solvent, the fat-cell appears as a connective tissue corpuscle
of which the cytoplasm is converted into a large vacuole.
The analogy between fat-cell and gland-cell, e.g. hepatic cells,
is obvious. As the one stores up sugar in the form of glycogen, so
the other collects fat. The sole difference is that in the liver-cell
the glycogen is arranged as a hyaline mass between the granules
and the network of cytoplasm ; in the fat-cells, on the contrary,
the fat flows together in a single mass, forming a large vacuole in
the midst of the cytoplasm and pushing the nucleus of the cell to
the periphery.
The analogy between the liver -cells and fat -cells is more
striking when we reflect that both have, respectively, the power,
not only of storing up the carbohydrates, or the fats, of alimentary
origin, but also of forming these substances by their specific
metabolic activity from other materials.
The ordinary plan of fattening stock-animals, e.g. pigs and
geese, with an excess of carbohydrate food, in which there is
little fat, shows plainly enough that not the whole of the fat
accumulated in the body, but only a small fraction of it, is
derived from the fat given in the diet. Moreover, we must take
into account that the fat accumulated in different animals differs
somewhat in its composition. It consists mainly of olein, palmitin,"
and stearin, in variable proportions, with small amounts of the
glycerides of butyric, capronic, caprylic, and other fatty acids,
united with a little phosphorated substance (lecithin and jecorin)
and also cholesterol, which, while it has some of the properties of
the fats, belongs by its 'Constitution to the alcohol group.
Owing to the different proportion in which olein, palmitin, and
stearin are present, the body fat of different animals is distinguished
by different melting-points. Thus the subcutaneous fat of man
melts at 15-20° C., that which surrounds the kidneys only at 25° ;
the fat of dogs at 22° ; of ducks at about 28° ; of the ox at about
40° ; of the sheep at 50° : olein, which melts most readily, pre-
dominates in the first ; stearin, which is least fusible, in the last.
This different constitution of the fats depends, not on differences
of diet, but on the differences of metabolic activity in the living
cells by which it is formed. The diet can in fact be considerably
varied, without perceptibly affecting the composition of the fat re-
serves in different animals. Owing to this fact, i.e. that the fat of
each species of animal has a definite melting-point, it was long held
that alimentary fat did not give rise directly to the fat of the body.
This, however, was proved by subsequent researches to be erroneous.
Klihne suggested as a decisive experiment in regard to the
origin of tissue fat from alimentary fat, that it might be possible
to get some fat extraneous to the body stored up by alimentation.
326 PHYSIOLOGY CHAP.
Lebedeff and I. Munk, and still more G. Eosenfeld (1899), suc-
cessfully performed this experiment, which others had attempted
with doubtful results. Lebedeff succeeded in making two dogs
which had previously fasted for some time store up linseed oil in
the one case, mutton fat in the other. In the same way I. Munk
found rape oil and mutton suet in the fat of dogs after feeding
them with these substances. In man, too, he succeeded in
showing that extraneous fatty acids could be stored up in the form
of neutral fats. Eosenfeld not merely noted in dogs an abundant
storing up of mutton fat and cocoa butter, but was able, even after
a month in which these fats had not been administered, to
demonstrate mutton fat almost in the pure state in the animal's
body.
The greater part of the fat stored up as reserve material in
the body, with the exception of the little derived immediately
from the alimentary fats, may be referred to the carbohydrates
or the proteins. Liebig, on the strength of a number of observa-
tions, particularly that bees fed on honey only, in which there is
very little protein, produce large quantities of wax, proposed the
theory that the greater part of the fat stored up in the body is
derived from carbohydrates. On the other hand, many other
observations to hand show that fats may arise from cleavage of
the complex protein molecule, when the nitrogenous group gives
rise to formation of urea, and the non-nitrogenous group to the
formation of fatty acid. The so-called fatty degeneration of the
tissues, in which the cytoplasm is converted into fat granules, is
a sufficiently cogent proof of this theory. The " maceration " of
cheese due to Penicillium glaucum is known to consist in a process
in which calcium paracasein decomposes with formation of fats,
ammonia, and other nitrogenous substances, which are found in
macerated cheese.
A more direct proof of the derivation of fat from protein was
adduced by Bauer (1878) from slow phosphorus poisoning, which
produces fatty degeneration of all the tissues in different degrees.
When a dog had lost the whole of its nitrogen and carbon by
fasting, he began to inoculate it subcutaneously with minute
doses of phosphorus dissolved in oil. After several consecutive
days, the daily amount of nitrogen excreted with the urine was
doubled, while the elimination of carbon and absorption of oxygen
were diminished by half. Phosphorus poisoning, therefore, doubled
the consumption of protein, \vhile the non-nitrogenous groups of
the protein molecule were stored up as fat. In fact, the post-
mortem showed fatty degeneration of all the organs. Bauer found
424 per cent fat in the dry substance of muscle, 30 per cent in
dry liver, while normally the first contains only 16 '7 per cent, and
the second only 10'4 per cent fat. We may, therefore, conclude that
fat is formed from protein in phosphorus poisoning.
v INTERNAL EESTITUTIVE SECEETIONS 327
These results were, however, submitted to more rigorous
examination by other workers (Klaus, Legert, Athanasiu, Lebedeff,
Kosenfeld). They have proved that in so-called fatty degenera-
tion, particularly from phosphorus, there is at first not an increase,
but a diminution of the total amount of fat in the body. In
the majority of organs the amount of fat has not increased, and
where it has augmented (liver) this occurs by migration of fat
from the adipose tissues. In fact, if a dog has previously been
fattened up with mutton suet, the fat extracted from the liver
degenerated by phosphorus shows the characteristics of mutton fat.
That fat can be formed from protein under normal conditions was
shown by Pettenkofer and Voif (1862, 1870, 1871), by experiments
on dogs kept on a full flesh diet. They estimated the total
intake and output of nitrogen and carbon, using as a criterion of
the carbohydrate metabolism the carbonic acid exhaled by the
animal into the large respiratory apparatus, invented by these
authors, of which we shall speak in treating of general metabolism.
They found that the whole of the nitrogen from the flesh of the
diet is excreted with the urine ; on the other hand, a considerable
amount of carbon remains in the body, either in the form of fat
(as supposed by the two Munich workers) or in the form of
glycogen (as others more correctly assumed).
Pfliiger, however, who did not admit the derivation of fat from
natural protein, succeeded in showing that the carbon of the
body was not derived from the proteins introduced, but from the
glycogen and fat simultaneously administered. The quotient
C/N was calculated too high by Pettenkofer and Voit. This was
explicitly recognised in subsequent work by E. Voit, Cremer,
Kumagawa.
Liebig's theory of the derivation of fat from carbohydrates
remained unshaken till Voit proposed to explain the fattening of
animals by hyperalimentation with carbohydrates, on the theory
of "sparers," i.e. by assuming that carbohydrates diminish the
normal consumption of fats, which therefore accumulate in the
body.
Later work has, however, shown the earlier theory to be
correct, i.e. that the larger part of the fat stored up in the
body originates in the carbohydrates. I. Munk (1885) repeated
on a dog the experiment of Fr. Hofmann, causing it to
consume all its fat in a 31 days' fast, and then nourishing it
on a minute amount of flesh and with increasing quantities of
starch and sugar. After 24 days the animal was killed, when he
found that it contained 960 grms. fat, only 172 grms. of which
could be derived from the flesh ingested ; the other 788 grms.
could only be formed from the carbohydrates, of which, according
to Munk's calculations, 8'3 per cent had been converted into fat.
N. Tscherwinsky (1883) performed a more rigorous experiment
328 PHYSIOLOGY CHAP.
on two young pigs of ten weeks, born in the same litter and of
equal weight. One was killed to determine the amount of fat
and nitrogenous substances contained in its whole body. The
second was kept alive four months, and constantly fed on barley,
which was chemically analysed. The total amount of fat and
nitrogenous substances were then estimated in this pig also, and
it was found that in four mouths, at most, 1560 grms. protein and
8560 grms. fat had been formed. Taking into account the whole
amount of protein and carbohydrate absorbed from the gastro-
intestinal canal, it was found that the animal had consumed
5930 grms. protein and had formed 7900 grms. new fat. Since
only the least part of this large amount of fat could derive from
the alimentary proteins consumed, it followed that the greater
part of it came from the carbohydrates.
Another definite proof of the direct formation of fats from
carbohydrates was furnished by Meissl and Strohmer (1883), who
experimented on a pig one year old, which they fed for a week
on rice, with simultaneous estimations of the intake and output
of nitrogen and carbon. Other similar proofs were given by
Eubner (1886), who experimented on a dog fed after two days'
fast on cane sugar and starch. Thus not only herbivora but
carnivora also are able to form fat directly out of carbohydrates.
From the chemical point of view — as was remarked by Bunge
— the formation of fat from carbohydrates is an enigma. The
fact is, however, well established experimentally, and is one of
the clearest examples that the cells of animal tissues are capable,
no less than those of plant tissues, of very complex synthetic
processes.
XIII. We have seen that the synthetic reconstitution and
polymerisation of the principal digestive products of protein, the
proteases and peptones, is the function of the columnar epithelium
which lines the gastro-intestinal canal. These substances, therefore
(which are the true compensation products for the losses suffered by
the living protoplasm in the performance of its functions), penetrate
into the circulating fluids of the tissues in the same form as that
in which they are found in the plasma of the blood and lymph.
Although not experimentally demonstrated, it is highly probable
that the greater part, if not the whole, of the proteins introduced
with the food reach the circulation in the form of serum albumin.
Owing to the marked tendency of the body to maintain the
constitution of the circulating fluids almost constant, the sum of
the protein absorbed after each meal does not accumulate in the
blood, but is at once stored up in the various tissues, where it
undergoes further transformations, either by forming more com-
plex syntheses and entering into the Living protoplasm, or by
undergoing a series of retrograde changes in which the whole of
its potential energy is utilised under different forms by the body.
v INTEENAL EESTITUTIVE SECRETIONS 329
Unlike carbohydrate and fat, the protein of alimentary origin
cannot, outside very restricted limits, be stored up in the body in
a stable form. In fact, under normal conditions, and with a
regular diet, the adult organism excretes during the day (in the
form of urea and other nitrogenous waste products) approximately
the same amount of nitrogen as is introduced with the food, apart
from that which leaves with the faeces. The slight up and down
variations of the absorbed as compared with the excreted nitrogen,
the plus or minus that can be noted from day to day on a
sufficient diet, do not accumulate but tend towards compensation,
so that an almost perfect equilibrium of metabolism is obtained,
on comparing the sum total of the nitrogen introduced and
that given off in the space of a few days. Elsewhere we shall
discuss fully the modifications of the organic balance in regard to
the different individual conditions and the varying nature and
quantity of the food.
Here we must confine ourselves to insisting on the fact that
while there is normally present in the tissues of the body a certain
provision of non-living protein, which constitutes a reserve of
nitrogenous material which can be utilised during a fast, and
readily replaced on the ordinary diet, this provision is invariably
confined within strict limits, so that it is not possible to increase
it (as can be done for fats, and to a certain extent for carbo-
hydrates) by an exuberant or luxus diet of nitrogenous substances.
Within physiological limits we constantly see that as the protein
introduced in the diet increases, so the amount of nitrogenous
waste products eliminated by the kidneys rises in proportion.
This practically complete independence from the daily supply
of nitrogenous foods of the reserve protein stored up in the tissues,
shows clearly that only a minimal part of the total amount of
alimentary protein reaching the circulation is converted by the
anabolic activity of the cells into living matter, to repair the
perpetual losses suffered by the cytoplasm in its intimate structure
—the greater part (which fluctuates enormously according to
the poverty or excess of the habitual diet) being consumed by
the katabolic activity of the tissues before it can become part of
the bioplasm. So that the nitrogen of the waste products daily
excreted comes to a large extent directly from the nitrogen of
alimentary protein.
The process by which the consumption of alimentary protein
takes place within the tissues is quite unknown to us. We can
only state that it differs essentially from that by which protein
is broken up in the gastro- intestinal canal by the action of
the digestive enzymes. According to Neumeister (1890), living
tissues never convert protein into proteoses and peptone. We
have seen that the protein in the liver gives rise to the
nitrogenous and sulphur-containing constituents of the bile, which
330 PHYSIOLOGY CHAP.
are eliminated by external secretion, also perhaps to a simultaneous
production of glycogen, which accumulates in the cytoplasm and
is slowly elaborated and poured out into the blood in the form
of glucose. Protein undergoes a different conversion in each
glandular organ that has a specific function. We are more or
less acquainted with the end-products of these hidden processes,
but of the intermediate links forged within Ihe cytoplasm we
know nothing.
We do not know definitely whether the reserve protein of
alimentary origin is equally distributed throughout the whole of
the cytoplasm, or whether (as for fat and glycogen) there are
organs and tissues which store it up in larger amount, and may be
regarded as special reserves. It seems probable that the lymph
organs serve as such a storehouse, since, as Fredericq noted, they
shrink in volume more than the other organs during fasting —
the liver excepted, which in starvation consumes the whole
of its stored-up glycogen, and is greatly reduced in weight and
volume.
We know that vegetable protoplasm, either with or without
chlorophyll, is able to nourish itself and to develop, at the expense
of the materials which it draws from the inorganic world. Plants,
in other words, are capable of manufacturing by synthesis from
the elements, or the very simple compounds which they obtain
from the earth, air, and water, the whole of the organic substances
— carbohydrates, fats, and proteins — which enter into the composi-
tion of their tissues. Is it possible that the same phenomenon, in
a minor degree and starting from less simple compounds, takes
place in the animal organism also ? We have seen that animal
amylogenesis and adipogenesis can occur either by synthetic
processes, which start from, the glucose, or by analytic processes, i.e.
cleavage of the protein molecule. Is animal protoplasm also able
to effect synthesis of the protein molecule from the nitrogenous
(amino-acids) and non-nitrogenous groups into which it has been
broken up ?
The whole of the protein stored up in the animal body
is usually held to be of alimentary origin, the total nitrogen
eliminated in the urine being taken as the measure of its con-
sumption. But although this theory has been uncontested, it
is founded on no direct experimental evidence. It is not
so much a true scientific theory as a physiological dogma,
deduced from the ancient doctrine of the antagonism between
plant and animal organisms — which is no longer tenable to-day.
When we discuss the metabolism which underlies muscular
activity and muscular work, we shall have to examine a fact which
seems to give countenance to this doubt, and to admit the
possibility of animal proteinogenesis.
O. Loewi (1902) succeeded in giving a direct experimental
331
foundation to this theory of proteinogenesis. On feeding dogs
with starch and cane sugar, together with the soluble nitrogenous
substances of the pancreas — digested until the biuret reaction
completely disappears — he found that the animals were not only
capable of maintaining their nitrogenous equilibrium, but were
also able to store up a considerable amount of nitrogenous
substance.
This process of the reconstruction of proteins by the combin-
ing together of amino-acids with loss of water (polymerisation) is
made more intelligible by the recent work of Emil Fischer,
who (as stated in Vol. I. p. 28) succeeded by the synthesis of
different amino-acids in obtaining much more complex compounds,
which he termed polypeptides. In some of their properties these
resemble the proteins.
XIV. To complete this chapter we must draw attention to
certain important experimental data, which show that the epi-
thelial cells that line the gastro-intestinal canal have (like the
hepatic cells), besides the secretory function we have discussed, a
protective function. By this they are able to dimmish or inhibit
the effects of toxic substances, whether introduced from without
or formed within the body, especially in the intestinal canal,
owing to the processes of digestion and putrefaction which take
place there. This protective function is more particularly built
up on that capacity for physiological selection by which the
epithelia of the intestine, while they absorb certain substances (in
defiance of the laws of osmosis) that diffuse with difficulty, do not,
on the other hand, permit others to pass which are more diffusible.
This selective capacity, of course, has a limit, otherwise intoxica-
tion by gastro-intestinal paths could not take place, — which is an
obvious absurdity. It is certain that many poisons of the category
of alkaloids produce a greater toxic effect when injected under the
skin than when administered by the mouth. It is often found
that the lowest lethal dose, as given hypodermically, is innocuous
or far less harmful when swallowed. M. Schiff (1861) and
F. Lussana (1864) were the first to demonstrate this point.
The phenomenon depends not merely upon the slow rate at
which alkaloids and other toxic substances are absorbed by the
intestinal epithelium, but also on the fact that after absorption
they pass by the roots of the portal system to the liver, where
they are arrested by the hepatic cells, which store up the alkaloids
in their cytoplasm, partly destroying them, partly restoring them
to the intestine with the bile, and partly discharging them by the
hepatic veins to be eliminated by the kidneys. Schiff actually
found the fatal dose of narcotic poisons to be much lower when
they were introduced hypodermically, than when they were
injected directly by the portal vein. He further found that a
frog, in which the vessels to the liver had been tied, died after the
PHYSIOLOGY CHAP.
subcutaneous injection of -^ of a drop of nicotine, while a
normal frog survived this dose without exhibiting the charac-
teristic symptoms of poisoning! Lastly, he saw that if the
hepatic parenchyma were triturated with alkaloids (nicotine or
hyoscyamine) the resulting extract had no toxic action on dogs.
This power of the liver to destroy or diminish the toxic action of
alkaloids does not hold for other organs. On triturating the
substance of the kidneys, e.g., with alkaloids, the latter keep their
toxic efficacy intact.
Mineral poisons, again, can be partially absorbed and retained
in the liver cells, whence they are slowly turned out into the
intestine by means of the bile. Orfila was the first who drew
attention to this fact, subsequently confirmed by all toxicologists.
Compounds of lead, copper, arsenic, iron accumulate in the liver
in preference to any other organ. Special physiological import-
ance attaches to the absorption and storage of iron in the liver,
a fact correctly interpreted by Lussana in relation to the
haernatogenic or haemoglobinogenic action of medicinal prepara-
tions of iron. In confirmation of this statement, Marfori (1893),
in Schmiedeberg's laboratory, found a special iron-protein com-
pound in the liver, to which he gave the name of ferratin,
analogous with the liaematogen which Bunge discovered in the
yolk of egg, neither of which gives a direct iron reaction, when
treated with ammonium sulphate.
Heger (1873-77) demonstrated the antitoxic action of the liver
by artificial circulation in the excised organ of defibrinated blood,
to which nicotine had been added. He observed that this blood
lost its characteristic odour after passing through the liver, the
alkaloid being partly retained by the liver cells. In subsequent
experiments he found that the liver was capable of absorbing
and retaining 25-50 per cent of the alkaloids passed through it
(strychnine, quinine, morphine, and nicotine), while none were
retained by the lungs, and very little by the muscles.
In accordance with Schiffs observations, Lautenbach stated
that one drop of nicotine sufficed to kill a large dog, with manifesta-
tions of tetanus, when the injection was made into the general
circulation, while two drops could be injected into the mesenteric
veins without inducing death or symptoms of tetanus, simple
phenomena of narcotic poisoning only being manifested. From
this Lautenbach concluded that nicotine contains two toxic
groups, one of which alone (i.e. that which produces tetanus) is
retained by the liver. Eene opposed these conclusions on the
strength of new experiments.
More extended researches with a larger number of alkaloids
were made by Jacques, and particularly by Koger (1886, 1887, 1889,
1892), in support of the theory that the liver stored up and partially
transformed the poisons that reached it from the digestive canal
v INTERNAL RESTITUTIVE SECRETIONS 333
by the portal system. The following only of Roger's conclusions
need be cited : —
(a) Dogs in which the portal vein has been tied, die after
injection of 3 ingrms. nicotine per kilo, body-weight, while normal
dogs exhibit only transitory disturbances after injection of 5mgrms.
(&) Solutions of salts of quinine, morphine, atropine, curare,
alcoholic extracts of putrid lluids, when freed from potassium
salts and injected into the intestinal veins of rabbits, show a
toxicity less by half than on injection into the peripheral veins.
(c) The liver retains ethylic alcohol, but not glycerol, acetone,
or inorganic substances in general. Ammonium carbonate is,
however, no less toxic when it passes through the liver.
(d) The venous blood from the systemic system and from the
hepatic veins of dogs is much less toxic, when defibrinated and
injected into the veins of rabbits, than the blood from the dogs'
portal vein. This higher toxicity of the portal blood seems due
to the products of intestinal putrefaction, since it disappears
after repeated disinfection of the intestine with napthaline and
iodoform.
(e) The liver is capable of partially converting toxins. If
fresh hepatic tissue be pounded up with nicotine and then
extracted with dilute, boiling sulphuric acid, only a part of the
poison is recovered.
(/) The liver degenerated by phosphorus poisoning, or cirrhotic
from ligation of the bile-duct, is no longer capable of exercising
any protective action against poisons. The same is true of the
liver of animals which have lost their glycogen after fasting.
In foetal development also the appearance of the protective action
of the liver coincides with accumulation there of glycogen.
Verhoogen (1893) arrived at other new data which show that
the depurating action of the liver does not depend solely upon its
position, and is not merely exercised upon the toxic substances
formed in the digestive apparatus. He found that on injecting
strong doses of morphine (5 to 6 grms. hydrochlorate) into the
jugular vein of dogs, and killing them at different times, the
alkaloid accumulated preferentially in the liver, bone marrow, and
spleen, whatever the interval from the diffusion of the poison.
This preferential accumulation of the alkaloids in these organs
does not depend on their content of blood, because the percentage
of toxin is less in the blood.
Verhoogen obtained the same results with sodium iodide, and
with small amounts of other substances, within physiological
limits.
To prove that the liver has the property of modifying certain
alkaloids, he mixed solutions of hyoscyamine with extract of
frogs' liver, and found that this substance lost all or almost all its
property of dilating the pupil. Bile has not the same property,
334 PHYSIOLOGY CHAP.
which is due to an unknown capacity of conversion by the
hepatic cells.
F. Schupfer, under Colasanti's directions, made equally
interesting observations on dehepatised as compared with normal
frogs, in regard to the toxicity of alkaloids inoculated beneath the
skin of the back. He was able to demonstrate that the liver
reduces the toxicity of cocaine hydrochlorate by -f ; of neutral
sulphate of atropine by about i ; of apomorphine hydrochlorate by | ;
of pilocarpine hydrochlorate by |.
Many other experiments were made by other workers, with
the object of discovering whether, under conditions in which the
liver is unable to function properly, either in pathological states or
after operations, the toxicity of the urine increases abnormally.
The results of Eoger (1886), Surmont (1892), Bellati (1893),
Villetti (1893), Bisso (1895), tend to show that the toxicity of
urine is more or less proportional to the gravity of the anatomical
and functional lesions of the liver.
Bisso's work, under the direction of Colasanti, seems the most
definite. He operated on dogs by gradual occlusion of the portal
system (Bernard-Ore method), collected the urine, and deter-
mined its toxicity by Bouchard's method of injection into the
veins of rabbits.
He found that the toxicity of the urine varies in normal dogs
with the diet. It is maximal with a flesh diet, minimal with a
milk diet, intermediate on a diet rich in fats. After occlusion of
the portal vein, urinary toxicity is tripled, while the original
ratio between the several diets persists. The liver accordingly
functions as a protective organ in the body, by arresting and
destroying the toxic substances formed during the secretory,
digestive, and putrefactive processes of the alimentary canal. A
strict functional relation between the liver and kidneys must also
be admitted, since, when the protective function of the liver is
in abeyance owing to occlusion of the portal vein, the kidneys
function more actively, and expel the toxic substances accumulated
in the body.
In order to define the nature of the protective function
normally exercised by the liver against the toxic products that
enter through the portal roots, Schroder and Salomon established
an artificial circulation in the liver, and made a chemical analysis
of the blood before and after it passed through this organ. They
saw that on adding ammonium carbonate to the blood, it was con-
verted into urea after circulating through the liver. This con-
version is due to a synthetic process effected by the hepatic cells,
in which the ammonium carbonate loses water and is converted
into urea. This conversion does not take place if the blood is
circulated through the kidneys or muscles.
After excision or ligation of the liver in geese, Minkowski
v INTEENAL EESTITUTIVE SECEETIONS 335
observed a marked increase of ammonia in the urine, associated
with a considerable diminution of uric acid, which (as we shall see
elsewhere) takes the place in birds of the urea of mammals.
These data show that the depurative action of the liver upon
the ammoniacal compounds developed in the digestive apparatus of
mammals and birds, consists in their synthetic conversion into
urea or uric acid, respectively.
Hahn, Massen, Nencki and Pawlow (1892) deflected the portal
circulation from the liver by joining the portal vein, which had
previously been tied near the hilum of the liver, with the inferior
vena cava. This ingenious experiment was first carried out by
Eck in 1877, and afterwards repeated by Stolnikow, when some of
the operated dogs survived. Those which survived the experi-
ments of the Eussian investigators exhibited phenomena of auto-
intoxication towards the tenth day from the operation — consisting
in sensory and motor disturbances, which developed into clonic
and tetanic convulsions, recurring in spasms. The excitatory
phenomena were succeeded by a cofnatose period in which some
animals died, while others recovered comparative health. Careful
observation showed that these attacks of auto-intoxication were
exhibited by the dogs that had eaten most meat. Pawlow and
Massen induced similar attacks in operated dogs by forced feeding
with an excessive quantity of nitrogenous foods.
When Nencki and Hahn (who took charge of the chemical part
of the work) discovered a large amount of carbamic acid in the
urine of the operated dogs, it occurred to Pawlow and Massen to see
whether the phenomena of intoxication were due to this abnormal
product, which would under natural conditions be converted by the
liver. On injecting carbamate of sodium or calcium, to an amount
of 0'25 grm. per kilo, body-weight into the veins of a normal dog,
they noted nervous disturbances similar to those seen in dogs with
Eck s fistula, while the same salt introduced into the alimentary
canal was innocuous, even in larger doses. They noted, further,
that the administration of sodium carbamate by the mouth, even
in smaller doses, in dogs with Eck's fistula, produced a similar
poisoning to that obtained with a flesh diet. From this they
concluded that the toxic agent which produces the spasms of auto-
intoxication in the operated dogs is represented by the carbamic
acid, which is normally neutralised by the hepatic cells, and gives
rise to the formation of urea, carbonic acid and water, according
to Drechsel's theory. The Eussian experimenters confirmed this
conclusion by excising a large part of the liver in dogs with Eck's
fistula, and tying the hepatic artery, when a comatose state was
at once produced, followed by strong convulsions which led to
death after 6-12 hours.
The liver in animals with Eck's fistula was found to be
atrophied, with partial fatty degeneration. The kidneys showed
336 PHYSIOLOGY CHAP.
albuminoid degeneration of the epithelia, due to accumulation in
the blood of toxic waste-products.
The urine of operated as compared with normal dogs proved to
contain carbamic acid, which was either entirely absent in normal
urine (Drechsel and Abel) or occasionally present in minute
quantities (Hahn and Nencki). The urine of the operated dogs
further showed a distinct reduction in the urea content,
associated with a constant increase of uric acid and ammonia.
These facts, which agree with the theory that the greater part of
the urea is formed in the liver, show that in all probability a
considerable part, if not the whole, of the carbamic acid is a
product of the conversion of nitrogenous substances effected by the
spleen, pancreas, and walls of the intestinal tract, which, when
normally conveyed to the liver by the portal system, gives rise to
the formation of urea.
Nencki, Pawlow, and Zaleski (1896) arrived at very important
results in a series of observations on the ammonia content of the
blood and other organs, and the formation of urea in mammals.
They found that the portal blood in dogs fed on flesh contains
five times as much ammonia as arterial blood, twice as much as
venous blood. On the other hand, the ammonia content of the
blood of the hepatic veins is approximately equal to that of
arterial blood. They further showed that the amount of ammonia
varies in the blood of the different roots of the portal system ; it
is maximal in the gastric mucous membrane, and largely exceeds
the quantity found in the contents of the stomach. On the other
hand, the ammonia content of the intestinal mucous membrane
and of the intestinal contents is approximately the same. It
diminishes in starvation, and still more on a mixed non-flesh
diet of bread and milk. Ammonia seems to be a metabolite
of the digestive glands, because the same quantity is found in
the gastric mucosa of a dog fed abundantly on flesh, and of
another dog, with a gastric and oesophageal fistula, subjected to
" sham feeding." Lastly, these experimenters found in a dog
with Eck's fistula that the ammonia content of the blood increases
to a marked extent during a flesh diet (as compared with a diet
of bread and milk), this increase becoming larger in proportion as
the symptoms of auto-intoxication are aggravated.
From their results as a whole these authors concluded that
owing to the function of the gastric and intestinal glands
(including the pancreas), an enormous amount of ammonia is
produced, which is stored up in the liver, where it is converted
into urea. According to them, the larger part, if not the whole,
of the urea originates in the metabolism of the glands, which
differs from that of the muscles, the liver being thus the most
efficient defence of the body against intoxication due to ammonia
and carbamic acid.
v INTERNAL EESTITUTIVE SECRETIONS 337
De Filippi's latest experiments (1899) on dogs with Eck's
fistula partially confirm the results of the Kussian school. De
Filippi states that with a mixed diet dogs are able to live for
months in good condition, and even to put on weight. When fed
with raw meat, they suffer after 2-3 days from vomiting, and
refuse their food. If forced to swallow it, the phenomena of auto-
intoxication described by the Russian observers set in on the third
or fourth day. But as compared with these cases, he noted others
in which even a protracted flesh diet produced no disorder, or at
most a general progressive emaciation. The season apparently
has great influence on the acute or chronic effects of an Eck's
fistula. In winter acute intoxication never fails, and may even
appear with a mixed diet ; while in summer some cases are re-
fractory to poisoning, even with a continuous flesh diet. The
intoxication produced by raw meat does not depend, according to
De Filippi, on the amount of nitrogenous constituents, because a
vegetable diet rich in proteins, as well as meat extracted with hot
or cold water, produces no sign of poisoning. On the other hand,
concentrated aqueous solutions of meat produce toxic symptoms
after 4-5 days, which are fatal in a short time.
De Filippi's experiments on the metabolism of a number of
dogs with Eck's fistula led to very irregular results, which differed
considerably in different animals. The most remarkable pheno-
mena are as follows : —
(a) The total nitrogen eliminated with the urine is as a rule
much less than the nitrogen introduced with the food, even taking
into consideration that eliminated with the faeces. We do not
know the form in which this nitrogen is retained ; it does not
seem to be eliminated by the lungs in the form of ammonia.
(&) A marked diminution in the urea eliminated by the
kidneys corresponds with the retention of nitrogen, while the
ammoniacal nitrogen increases, and the uric acid is doubled or
even trebled.
(c) The nitrogenous extractives of the urine increase in dogs
fed on aqueous extract of meat, as compared with normal dogs, a
proof that they are either not converted into urea, or to a minimal
extent only.
(cT) In all fasting dogs provided with Eck's fistula, De Filippi
observed that the administration of 100 grms. glucose, lactose, or
saccharose is followed by glycosuria, which is not the case in
normal dogs. It appears half an hour after ingestion, and lasts
3-4 hours. With ingestion of glucose the glycosuria is less persistent
and less intense (O'2-l per cent). Sometimes it is entirely absent,
which may be explained as meaning that the glucose can be
converted into glycogen and stored up by the muscles as well as
the liver, to which it is conveyed by the blood of the hepatic
artery.
VOL. II Z
338 PHYSIOLOGY CHAP.
Post-mortem examination of operated dogs that have perished
from auto-intoxication show in addition to advanced atrophy of
the liver, a grave alteration of the renal parenchyma, probably
different in character from that of ordinary nephritis. This renal
alteration, however serious, is not accompanied by albuminuria.
Once only De Filippi found in the urine of a dog 0'05 grm. per
cent of albumin. Complete anuria may appear in the extreme
period of intoxication that precedes death.
This special renal alteration explains the whole of the irregu-
larities in the toxic phenomena presented by the different animals
operated on, which vary greatly in the different periods following
the operation. According to De Filippi the deflection of the
portal system from the liver includes the principal paths by which
the injurious metabolites absorbed by the intestine are rendered
innocuous by the liver. So long as the kidneys function normally,
the toxic circulating substances can be removed from the blood by
an excess of work of the kidneys. But this excess of work and
the constant passage of toxic substances finally affect the renal
parenchyma, so that compensation fails, and intoxication sets in.
The choice of diet is very important in delaying this renal
alteration ; a diet of raw meat is harmful, owing to the extractives
which it contains, since these produce rapid alterations of the
renal epithelia, and cause an accumulation of toxic substances
in the blood. Hence the importance of a milk diet in the treat-
ment of hepatic cirrhoses and nephritis.
The above data show that while many highly important
problems are still unsolved, the theory of the protective functions
of the liver is firmly based upon innumerable experiments, which
are of great interest, from both the physiological and the clinic
point of view.
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QUEIROLO. Atti dell' XI. Congresso med. internaz. iii., 1894.
MAGNANIMI. II Policlinico, iii., 1896.
F. SCHUPFER. Ibidem, 1896.
NENCKI, PAWLOW, and ZALESKI. Archiv fur experim. Pathol. und Pharmacol.
xxxvii., 1896.
DE FILIPPI. Arch. ital. de biologie, xxxi., 1899.
Recent English Literature : —
W. H. THOMSON. Contributions to the Physiological Effects of Peptone when in-
jected into the Circulation. Parts IV. and V., Journ. of Physiol., 1899-1900,
xxv. 1, 179.
T. LI. TUCKETT. Auto-intoxication as the Cause of Pancreatic Diabetes. Journ.
of Physiol., 1899-1900, xxv. 63.
W. E. RAY, T. S. MCDERMOTT, and G. LUSK. On Metabolism during a Combina-
tion of Phosphorus Poisoning and Phlorhizin Diabetes. Amer. Journ. of
Physiol., 1900, iii. 139.
F. W. PAVY and R L. SIAU. On the Question of the Formation of Sugar in boiled
Liver. Journ. of Physiol., 1901-2, xxvii. 457.
E. WAYMOUTH REID. Intestinal Absorption of Solutions. Journ. of Physiol.,
1902, xxviii. 241.
J. F. ARTEAGA. Phlorizin Diabetes in Cats. Amer. Journ. of Physiol., 1902,
vii. 173.
A. S. LOEVENHART. On the Relation of Lipase to Fat Metabolism. Lipogenesis.
Amer. Journ. of Physiol. , 1902. vi. 331.
L. B. STOOKEY. On the Formation of Glycogen from Glycoproteids and other
Proteids. Amer. Journ. of Physiol., 1903, ix. 138.
J. P. UNDERBILL. New Experiments on the Physiological Action of the Proteoses.
Amer. Journ. of Physiol., 1903, ix. 345.
Y. HENDERSON and A. L. DEAN. On the Question of Proteid Synthesis in the
Animal Body. Amer. Journ. of Physiol. , 1903, ix. 386.
F. W. PAVY, T. G. BRODIE, and R. L. SIAU. On the Mechanism of Phloridzin
Glycosuria. Journ. of Physiol., 1903, xxix. 467.
B. MOORE. On the Synthesis of Fats accompanying Absorption from the Intestine.
Proc. Roy. Soc., 1903, Ixxii. 134.
v INTEENAL KESTITUTIVE SECEETIONS 341
S. P. BEEBE and B. H. BUXTON. The Production of Fat from Proteids by the
Bacillus pyocyancus. Amer. Journ. of Physiol., 1908, xii. 466.
J. E. SWEET. The Artificial Anastomosis between the Portal Vein and the Vena
Cava Inferior. Eck's Fistula. Journ. of Experim. Medicine, 1905, vii.
P. W. COBB. Some Observations on the Carbohydrate Metabolism in partially
depancreated Dogs. Amer. Journ. of Physiol., 1905, xiv. 12.
L. B. MENDEL and F. P. UNDERBILL. On the Paths of Absorption from the Liver.
Amer. Journ. of Physiol., 1905, xiv. 252.
F. P. UNDERBILL. Certain Aspects of Experimental Glycosuria. Journ. of Biol.
Chem., 1905-6, i. 113.
E. P. CATHCART and T. B. LEATHES. On the Absorption of Proteids from the
Intestine. Journ. of Physiol. , 1905-6, xxxiii. 462.
T. SOLLMANN. Observations on Human Chyle. Amer. Journ. of Physiol., 1906-7,
xvii. 487.
M. H. FISCHER and G. MOORE. On Glycosuria and the Alimentary Excretion of
Carbohydrates. Amer. Journ. of Physiol., 1907, xix. 314.
J. J. R. MACLEOD. Studies in Experimental Glycosuria. I. On the Existence of
afferent and efferent Nerves, etc., etc. Amer. Journ. of Physiol., 1907, xix. 388.
A. E. TAYLOR. On the Synthesis of Protein through the Action of Trypsin.
Journ. of Biol. Chem., 1907, iv. 87.
T. B. ROBERTSON. Note on the Synthesis of a Protein through the Action of
Pepsin. Journ. of Biol. Chem., 1907, iv. 95.
W. SALANT. The Influence of Alcohol on the Metabolism of Hepatic Glycogen.
Journ. of Biol. Chem., 1907, iv. 403.
J. M. HAMILL. Observations on Human Chyle. Journ. of Physiol., 1906-7,
xxxv. 151.
J. LOCHHEAD and W. CRAMER. On the Glycogen Metabolism of the Foetus. Proc.
of the Physiol. Soc., 1906 ; Journ. of Physiol., xxxv. 11.
T. E. SWEET and P. A. LEVENE. Nuclein Metabolism in a Dog with Eck's Fistula.
Journ. of Experim. Medicine, 1907, ix. 2.
F. W. PAVY and H. W. BYWATERS. On Glycogen Formation by Yeast. Journ. of
Physiol., 1907-8, xxxvi. 149.
P. B. HAWK. On a Series of Feeding and Injection Experiments following the
Establishment of the Eck Fistula in Dogs. Amer. Journ. of Physiol., 1908,
xxi. 259.
W. SALANT. The Influence of Alcohol on the Metabolism of Hepatic Glycogeu.
Studies from the Rockefeller Inst., 1908, viii. 8.
G. LUSK. The Influence of Cold and Mechanical Exercise on the Sugar Excretion
in Phlorhizin Glycosuria. Amer. Journ. of Physiol., 1908, xxii. 163.
G. LUSK. The Production of Sugar from Glutamic Acid ingested in Phlorhizin
Glycosuria. Amer. Journ. of Physiol., 1908, xxii. 174.
L. B. MENDEL and TADASU SAIKI. Chemical Studies on Growth. IV. The Trans-
formation of Glycogen by the Enzymes of Embryonic Tissues. Amer. Journ.
of Physiol., 1908, xxi. 64.
J. J. R. MACLEOD. Studies in Experimental Glycosuria. II. Some Experiments
bearing on the Nature of the Glycogenolytic Fibres in the great Splanchnic
Nerve. Amer. Journ. of Physiol., 1908, xxii. 373.
J. J. R. MACLEOD and H. 0. RTJH. Studies in Experimental Glycosuria. III. The
Influence of the Stimulation of the great Splanchnic, etc. Amer. Journ. of
Physiol., 1908, xxii. 397.
T. C. BURNETT. On the Production of Glycosuria in Rabbits by the Intravenous
Injection of Sea- water made Isotonic with the Blood. Journ. of Biol. Chem.,
1908, iv. 57.
F. P. UNDERBILL and T. S. KLEINER. Further Experiments on the Mechanism of
Salt Glycosuria. Journ. of Biol. Chem., 1908, iv. 395.
W. CRAMER. On the Assimilation of Protein introduced Parenterally. Journ. of
Physiol., 1908, xxxvii. 146.
H. PRINGLE and W. CRAMER. On the Assimilation of Protein introduced Parenter-
ally. Journ. of Physiol., 1908, xxxvii. 158.
0. H. PLANT. Experiments on the Absorption of Fat from an isolated Loop of small
Intestine in healthy Dogs. Amer. Journ. of Physiol., 1908-9, xxiii. 65.
J. J. R. MACLEOD. Studies in Experimental Glycosuria. IV. The Cause of Hyper -
glycaemia produced by Asphyxia. Amer. Journ. of Physiol., 1908-9, xxiii. 278.
342
PHYSIOLOGY
CHAP. V
A. E. TAYLOR. On the Conversion of Glycogen into Sugar in the Liver. Journ. of
Biol. Chem., 1908-9, v. 315.
R. H. WHITEHEAD. A Note on the Absorption of Fat. Amer. Journ, of Physiol. ,
1909, xxiv. 294.
L. B. MENDEL. The Absorption of Fats stained with Sudan III. Amer. Journ. of
Physiol. , 1909, xxiv. 493.
V. H. MOTTRAM. Fatty Infiltration of the Liver in Hunger, Journ. of Physiol.,
1909, xxxviii. 281.
E. V. McCoLLUM. Nuclein Synthesis in the Animal Body. Amer. Journ. of
Physiol., 1909-10, xxv. 120.
E. P. CATHCART. The Influence of Carbohydrates and Fats on Protein Metabolism.
Journ. of Physiol., 1909-10, xxxix. 311.
D. NOEL PATON. Creatin Excretion in the Bird and its Significance. Journ. of
Physiol., 1909-10, xxxix. 485.
R. T. WOODYATT. Phlorhizin Glycocholia. Journ. of Biol. Chem., 1909-10, vii. 133.
J. J. R. MACLEOD and R. G. PEARCE. Studies in Experimental Glycosuria. VI.
The Distribution of Glycogen over the Liver under various Conditions. Post-
mortem Glycogenolysis. Amer. Journ. of Physiol., 1910-11, 341.
G. LUSK. The Influence of Cold Baths on the Glycogen Content of Man. Amer.
Journ. of Physiol., 1910-11, xxvii. 427.
T. LI. TUCKETT. On the Production of Glykosuria in Relation to the Activity of
the Pancreas. Journ. of Physiol., 1910-11, xli. 88.
E. P. CATHCART and M. R. TAYLOR. The Influence of Carbohydrate and Fat on
Protein Metabolism. II. The Effect of Phloridzin Glycosuria. Journ. of
Physiol., 1910-11, xli. 276.
N. B. FOSTER and H. L. FISHER. Creatin and Creatinin. Metabolism in Dogs
with Eck Fistula. Journ. of Biol. Chem.. 1911, ix. 359.
CHAPTEK VI
THE INTESTINE AS AN ORGAN OF EXCRETION
CONTENTS. — 1. Physical characters and chemical composition of faeces and
intestinal gases. 2. Alimentary residues and waste products in faeces, while
taking food and in fasting. 3. Formation of faecal masses a function almost
exclusively confined to small intestine. 4. Theory of normal human faeces.
5. Toxicity of faeces. 6. Mechanical and chemical functions of caecum.
7. Mechanism of defaecation. 8. Innervation. Bibliography.
WE have seen (in Chapters III. and IV.) that the character
common to all the chemical processes carried on in the alimentary
canal is the hydrolytic cleavage of the larger molecules of the
food-stuffs, by which these are reduced to smaller groups of atoms,
and become more soluble and diffusible. They are thus converted
into suitable material for the anabolic chemical activity of the
living protoplasm, and the synchronous and homologous (construc-
tive or reintegrative) changes within its cells.
In the last chapter, in discussing what is known of these
hidden processes, we followed the three different groups of organic
food-stuffs from the alimentary canal to the blood, and from the
blood to the liver, as well as to the other tissues and organs. We
found that the anabolic processes (both chemical and cytological)
precede or succeed — or in any case are intimately connected and
associated with — processes of the opposite or katabatic nature. In
these the nutrient substances, on penetrating into the protoplasm,
or before entering the structure of the living matter, for the most
part undergo a succession of retrograde chemical transformations,
by which they are ultimately reduced to waste products, destined
to be eliminated from the body as useless or injurious. This
disintegrative work of the tissues, in which the potential energy
of the restitutive substances of alimentary origin is liberated
under various forms, necessarily involves a certain consumption
and expenditure of living matter, which increases the sum of the
katabolic products.
The ultimate and simplest waste products of the animal
economy are : —
.(a) Urea, which is derived entirely from the consumption of
proteins, and is formed chiefly, if not exclusively, by the liver.
343
344 PHYSIOLOGY CHAP.
(5) Carbonic acid and water, which are produced by oxidation
of all three groups of organic food-stuffs, and are formed in every
living tissue-cell ;
(c) Salts, particularly phosphates and sulphates, which are
formed by oxidation of the sulphur of the proteins and the phos-
phorus of the nuclein, lecithin, and other phosphorated substances.
These final products of metabolism, together with many other
intermediate products of oxidation, are expelled from the body as
fast as they are formed, by the various organs of excretion — the
intestines, kidneys, lungs and skin.
The kidneys are the principal organs for the elimination of
waste products. They secrete urine, which contains the greater
part of the urea and other nitrogenous products, the greater part
of the salts, a very large amount of water, and a little carbonic
acid. The lungs (as we saw in Vol. I. Chapter xi.) eliminate
most of the carbonic acid formed in the tissues, along with a con-
siderable amount of water in the form of vapour. The intestine
and skin, although their excretory functions present some specific
characters, may undoubtedly be regarded as vicarious excreting
organs, which are complementary to the lungs and kidneys.
Intestinal excretion must be treated first, since it is a necessary
complement to the study in the three preceding chapters of the
functions of the digestive canal.
I. We have already considered the Intestine as an organ for
the digestion of foods, and absorption of the digestive products.
We now have to consider it as an organ for excretion, i.e. a canal
which collects a certain quantity of waste matter destined to be
periodically cast out of the body, in the form of the faeces or
excrements.
The investigation of the faeces — with as exact a determination
as is possible of their chemical constitution, their origin, and the
process by which the several products contained in them are
formed, together with the quantitative and qualitative variations of
the latter in relation to various forms of diet — is a subject of
great scientific interest, which has not hitherto received adequate
treatment.
The amount, physical characters, and composition of the
excreta differ widely in the different classes of animals, principally
'in relation to the nature of their diet. Herbivora excrete a much
larger amount of faeces than carnivora, because vegetable foods
(in comparison with those of animal origin) are much richer in
substances which are indigestible or difficult of digestion, so that
larger quantities have to be taken in to satisfy the needs of the
body, and a larger residue is left in the intestine. Man, who is
omnivorous, produces a variable daily quantity of faeces, according
as his diet is mainly vegetable or animal : with the first he normally
excretes a larger amount, with the second, a less.
vi INTESTINE AS AN OEGAN OF EXCEETION 345
Apart from the nature of the diet, the daily amount ingested,
in excess of certain physiological limits, alters the amount of the
faeces. A superabundant meal, although it may consist wholly of
digestible substances, gives rise to more excreta, because a more or
less considerable portion escapes the action of the digestive enzymes,
and fails to come in contact with the absorbing surface of the
intestine. In a mixed diet of normal amount, the weight of the
human faeces is about -f-i that of the ingested food (Liebig),
i.e. 120-150 grms. with 30-37 grms. solid substances (C. Voit).
The consistency of the faeces varies with their water content,
which generally fluctuates between 68 and 82 per cent, within
physiological limits, i.e. excluding cases of diarrhoea, in which there
is much more water. It depends less on the quantity of water
drunk than on the vigour of intestinal peristalsis, the tone of the
intestinal vessels, and the state of the epithelium by which intestinal
absorption is regulated.
The chemical reaction of the faeces varies greatly with the
scope and activity of the fermentative and putrefactive processes
in the different parts of the intestine, conditions which are not easy
to determine for individual cases. In the last part of the ileum
the reaction may be alkaline, neutral, or slightly acid; in the
large intestine it is usually distinctly acid. This depends, not on
acidity of the secretion from the mucous membrane (which is
alkaline, both in the small and in the large intestine), but on
acid fermentations in the faecal content i(due to the intestinal
bacteria which decompose the carbohydrates. This is proved by
the fact that the acidity of the faeces is greatest when the diet is
rich in starchy and saccharine substances.
The acidity of the faecal masses is mainly due to the presence
of lactic acid, derived from the lactic fermentation of sugar, the
vigour of which probably varies with the amount of carbohydrates
ingested and with other conditions of the intestinal tract, which
have not been exactly determined.
The neutral or alkaline reaction sometimes exhibited by the
faeces depends essentially on the putrefactive processes of the
proteins, which give rise to a development of ammonia.
The abundant secretion of mucus in the large intestine also
favours the neutral or alkaline reaction of the faeces.
The colour of the faeces varies considerably according to the
nature of the food. Contrary to the general opinion, the bile
pigments and their decomposition products have little influence on
the normal colour of the dejecta.
On an exclusive flesh diet the faeces, independent of the bile,
are blackish, owing to the presence of haematin and ferrous
sulphide. On an exclusive diet of brown or wholemeal bread they
are lighter in colour. On a diet rich in fat they are yellowish or
clay-coloured. In infants the greenish-yellow colour of the excreta
346 PHYSIOLOGY CHAP.
is partly due to biliverdin and bilirubin (Lesage), which are
normally reduced in adults.
The obnoxious odour of the faeces increases with the putrefac-
tive processes of the intestine, and depends principally on the
development of scatole (Brieger). With a flesh diet the faecal
odour is more pronounced than with a vegetable diet.
The chemical and morphological composition of the faeces are
so variable that it would be tedious to quote the analysis given for
individual cases. Halliburton distinguishes the following groups
of materials : —
(a) Undigested Food-stuffs. — Neutral fats, carbohydrates, and
also proteins with a superabundant protein diet. It should be
noted that unaltered protein is never found in the faeces with a
moderate diet (Hoppe-Seyler).
(b) Indigestible Food-stuffs. — Cellulose, keratin, mucin, nuclein,
chlorophyll, gum, resin, cholesterol, phosphates and other bases,
particularly calcium.
(c) Food-stuffs difficult of Digestion. — Granules of raw starch,
fragments of elastic tissue, tendon, cartilage and (especially with a
superabundant flesh diet) more or less unaltered muscle fibres.
(d) Waste Products of Food-stuffs. — Groups of aromatic sub-
stances (scatole, indole, phenol, etc.) formed by putrefactive pro-
cesses and probably tending, when formed, to check or arrest these
processes ; groups of fatty acids, (formic, acetic, butyric, isobutyric,
yalerianic, capronic acid, with others such as lactic, malic, succinic,
etc., in a free state or combined with ammonia and other bases) ;
haematin from decomposition of haemoglobin ; insoluble and non-
absorbable soaps of calcium and magnesium ; stercorin, which
according to Flint, is a decomposition product of cholesterol ;
excretin, as described by Marcet for human faeces, the composition
of which is wholly unknown. All these products originate not in
the activity of the digestive enzymes, but in the fermentative and
putrefactive processes effected by the intestinal bacteria.
(e) Substances converted and not reabsorbed, of the Bile and
other Intestinal Secretions. — Mucin, cholalic acid, cholesterol,
lecithin, which partly come from the foods, hydrobilirubin and
stercobilin, which are reduction products of the bile pigments, and
no longer give Gmelin's reaction. The co-operation of the pancre-
atic juice seems necessary in the formation of these pigments, since
in two cases of obstruction of Wirsung's Duct, Walker found no
stercobilin in the excreta, which had the clay colour characteristic
of the faeces in jaundice, although the liver was healthy and the
bile flowed freely into the intestine.
(/) Bacteria of different Kinds, Epithelial Cells and Detritus. —
Great quantities of bacteria are present, Bacterium coli commune
(as we have seen) largely predominating. The epithelial cells
shed by the mucous membrane are sometimes almost intact, the
vi INTESTINE AS AN OEGAN OF EXCEETION 347
striated border being still visible ; more often, however, they are
imperfect, or reduced to the bare nuclei.
This completes our definite knowledge of the composition of
human faeces, under normal conditions.
The development of gases in the digestive canal, which mix
with the air swallowed with the food and the saliva, is largely
associated with the complex process of formation of the faeces.
This development of gases arises from the fermentative and putre-
factive processes of the intestinal bacteria. It is therefore entirely
absent during intra-uterine life, when the contents of the intestine
are destitute of microbes. Since the development of gases is due
to decomposition of the various food -stuffs, it follows that the
gaseous mixture must vary in composition according to the nature
of the diet.
The oxygen of the swallowed air is entirely or almost entirely
absent in the intestinal canal, no doubt because it is rapidly
absorbed by the blood, through the mucous membrane which func-
tions as the respiratory surface. This absorption of oxygen with
simultaneous excretion of carbonic acid takes place almost exclu-
sively in the gastric cavity, where the presence of the hydrochloric
acid of the gastric juice normally checks any fermentation of the
chyme, with ebullition of- gases. The gaseous mixture in the
stomach, therefore, consists of the air swallowed with the food and
the saliva, and to a less extent of the duodenal gases, which may
penetrate the pyloric orifice, or diffuse through it. Planer found
in the gases of the dog's stomach 66-68 per cent nitrogen, 23-33
per cent carbonic acid, and only 0'8-6'1 per cent oxygen. These
data show that a respiratory exchange takes place in the stomach,
the oxygen of the air swallowed being absorbed by the blood
circulating in the capillaries of the mucous membrane, while the
carbonic acid of the blood passes into the air of the stomach, and
partially mixes with that which comes from the duodenal gases.
The gases of the intestinal contents were analysed by Planer in
the dog. They vary in composition in the small and large intes-
tine with a flesh and a vegetable diet, as shown by the following
table of volumetric percentages : —
Small Intestine.
Large Intestine.
Gas.
Meat.
(3 hrs. after).
Bread.
Vegetables.
Meat.
(3 hrs. after).
Vegetables.
C02
40-1
38-8
47-2
74-2
65-1
H2
13-9
6'3
487
1-4
2-9
H2S
—
—
—
0-8
—
02
0-5
07
—
—
—
N2
45-5
54-2
4-0
23-6
5-9
348
PHYSIOLOGY
CHAP.
Euge analysed the intestinal gases of man, as given off per
anum, with the following results : —
Milk Diet.
Flesh Diet.
Vegetable Diet
I.
II.
I.
II.
I.
II.
C02
16-8
9-9
13-6
8-4
34-0
21-0
CH4
0-9
—
37-4
24-4
44-5
55-9
H2
43-3
54-2
3-0
07
2-3
4-0
N2
38-3
367
45-9
64-4
19-1
18-9
C. S. Hofmann never detected methane or marsh gas in his
work on the intestinal gases of dogs and rabbits, but hydrogen
was constantly present, with traces of oxygen and sulphuric acid.
As shown by the tables, carbonic acid always occurs in large
quantities, particularly after a vegetable diet. It may be developed
by different processes, by cleavage of the alimentary carbonates,
lactates, acetates, and citrates ; by alcoholic fermentation of glucose;
by putrefaction of carbohydrates (particularly of cellulose) and
proteins; by butyric fermentation of lactic acid; lastly by
diffusion from the capillaries of the mucous membrane of the
intestine.
The hydrogen, which is present in large quantities, especially
in a milk diet, is undoubtedly due to the butyric fermentation of
lactic acid, during which carbonic acid and hydrogen are developed.
The methane, which is developed in man in large quantities
after a diet of meat and vegetables, while it is scanty in a milk
diet, originates in the decomposition of acetates and lactates
(Hoppe-Seyler) and of cellulose (Hoppe-Seyler, Tappeiner, Henne-
berg, and Stohmann) ; also to a small extent from the decomposi-
tion of the choline, derived from lecithin. It is difficult to explaii
the absence of methane in the intestinal gases of the dog an(
rabbit.
Nitrogen is always present, though it varies much in quantity
with different diets. For the most part it comes from the
swallowed air, left behind after absorption of the oxygen ; it may
arise partly, however, from diffusion through the wall of the intes-
tine (Bunge), and also from putrefaction of the proteins, witl
simultaneous development of ammonia.
The sulphuric acid, of which traces are normally present in tl
intestinal gases, originates undoubtedly in the putrefaction of
proteins, during which ammonia, sulphuric acid, ammonium
sulphate, fatty acids, amines and amino-acids (especially leucine
and tyrosine), and aromatic ethers (particularly indole, scatole,
phenol, and cresol) are developed.
vi INTESTINE AS AN OKGAN OF EXCBETION 349
II. The excreta which accumulate in the lower part of the
intestine accordingly comprise two kinds of substances : —
(a) Those derived from the food, i.e. indigestible or undigested
alimentary residues of ingesta, or non-absorbed and non-absorbable
decomposition products.
(&) Chemical compounds discharged from the wall of the
alimentary canal as secretory products of the adjoining glands,
which are not or cannot be reabsorbed by the lymph and blood ;
and detritus shed off in the epithelial regeneration of the mucous
coat.
The exact determination of the first group of substances is of
great importance in defining the digestibility, or better the more
or less perfect utility -value, of the individual food-stuffs. It is
clear that the less the amount and the simpler the chemical
composition of these products the more complete will be the utility
of any given diet.
The determination, on the other hand, of the total waste pro-
ducts in the second group, is more valuable in determining the
importance of the intestine as an organ of excretion ; also in decid-
ing whether the intestine expels specific products of metabolism,
and to what point it is able to assist or replace the excretory
function of the kidneys.
No exact distinction between the two kinds of substances has,
however, yet been possible, either because the analytical methods
at our disposal are inadequate for the quantitative determination
under different circumstances of the individual components of the
faeces (which, moreover, vary greatly even within physiological
limits), or because a considerable proportion of these can arise both
from decomposition of the food, and from katabolic processes in
the glands adjoining the intestinal canal, and in other tissues of
the body. "
A simpler problem, capable of experimental solution, is to
decide which of the two groups forms the largest and most
important part of these excreta, the alimentary residues, or the
residues of the intestinal secretions and epithelial detritus.
From the fact that in ordinary, normal faeces the residues of
the digestive secretions, especially bile and the epithelial detritus,
are present in small quantities only, it was formerly supposed that
the faecal mass consisted mainly of undigested alimentary residues.
C. Voit and his school (1860, 1884, 1892) first demonstrated the
fallacy of this theory.
Voit investigated the meconium, which is formed and collects
during intra-uterine life in the intestine. He also found that a
blackish, pitchy, faecal mass, similar to meconium, is formed in the
dog's intestine during a protracted fast. On a flesh diet, moreover,
similar faeces are formed in the dog, with the same characters as in
fasting ; the amount is scanty, sometimes increasing if more meat be
350
PHYSIOLOGY
CHAP.
given, but never in proportion with it. Meconium and the faeces of
fasting consist exclusively in the residues of the secretions poured
into the intestine, which contain certain metabolites that are
excreted neither by the kidneys nor by the skin and lungs. But
even on a strict flesh diet the faeces have, as a rule, the same
composition, a minimal amount of alimentary residues only being
visible under the microscope.
If sugar, starch, and fat be added to the flesh diet, the residues
of these substances appear in the faeces only when they are
administered in large quantities. So that on this mixed diet also,
the faeces consist mainly of the waste products of the digestive
secretions. It is only on feeding with certain foods that are very
rich in starch, e.g. bread and potato, that the faeces are found to
contain alimentary residues (for the most part little altered) along
with a reduced amount of metabolites.
These results were extensively confirmed in Voit's laboratory
by Fr. Miiller and Eieder (1882). This last author estimated the
amount of nitrogen found daily in the faeces and urine of both
dogs and man, on a diet entirely or almost entirely free from
nitrogenous substances ; and obtained results which induced him
to think it probable that not only in the dog but in man also
the faeces consist mainly of katabolic products, excreted by the
digestive organs. In fact, from three series of experiments on a
man fed on this regimen, he obtained the averages shown in the
following table : —
Series.
Nitrogen in Urine.
Faeces in Dried
State.
Percentage Nitrogen
Content of Faeces.
Total Nitrogen
Content of Faeces.
1
9'30 grins."
13 "4 grms."
4 '08 per cent'
0'54 grm/
2
9-50 „
•8-65
15'4 ,,
-14-7
5-69 „
5-27
0-57 „
073
3
7-16 „ .
13-4 ,,
5-85 „
0-78 ,,
So that on a non-nitrogenous diet a man (weighing about
kilos.) excretes a daily average in the faeces of 0-I73 grm. nitrogen
(an amount not much in excess of that excreted by a dog of 35
kilos., which on an average equals 0'64 grm.). This amount of
nitrogen represents about 8 per cent of the total nitrogen
eliminated by the body.
During an abundant mixed diet, man excretes on an average
2'53 grms. nitrogen in the faeces (Pettenkofer and Voit). Of this
nitrogen it is probable that 1*80 grms., i.e. 71 per cent, comes from
alimentary residues, and that 0'73 grm., i.e. 29 per cent, must be
referred to katabolic residues excreted by the intestinal canal. In
this case, therefore, the amount of alimentary residues in the faeces
vi INTESTINE AS AN OEGAN OF EXCEETION 351
exceeds that of the metabolites from the intestinal canal. But
with a diet consisting strictly of meat and eggs (according to
Buhner's experiments on man) 13-17 grms. dry faeces are ob-
tained, with only 0'6-l-2 grms. nitrogen. It is therefore highly
probable that human faeces, like the dog's, consist mainly of
metabolites from the alimentary canal.
A vegetable diet, particularly of vegetables and black bread,
increases the amount of faeces, with reduction of the percentage
quantity of nitrogen and rise of the absolute quantity. In fact,
(according to Eubner) the faeces for one day contain 2'4-4'3
grms. nitrogen.
Even during an absolute fast, a considerable amount of faecal
matter is formed in man, as shown by the interesting researches
of Fr. Miiller on the fasting men Cetti and Breithaupt, as well as
by our own observations on Succi during his fasts. The amount
of faeces in fasting is, however, considerably less for man than that
found by Voit for dogs and cats. Cetti during a fast of 10 days
excreted about 38 grms. faeces (when dried), i.e. 38 grms. per
diem: Breithaupt in 6 days' fast excreted only 12 grms. i.e. 2
grms. per diem ; Succi in 30 days' fast excreted 150 grms., which
corresponds approximately to 5 grms. per diem, a figure somewhat
higher than the preceding, because Succi frequently took mineral
waters while fasting.
Human faeces in fasting are yellowish-brown balls, of medium
consistency, with little odour, and resemble the faeces in a diet
consisting mainly of flesh.
The percentage nitrogen content of the faeces in fasting is
greater than while taking food. In Cetti it reached 8 '28 per cent,
in Breithaupt 5'67 per cent : while on an exclusively milk diet it
is 3'03-3'3 per cent ; with milk and white bread 3'92 per cent
(Fr. Miiller); with meat and bread 3'l-3'5 per cent (Meyer). It
is only on a strict flesh diet that we find 6-5-6'9 per cent nitrogen
(Eubner), a figure approximately equal to the nitrogen content of
the faeces in fasting. Since the daily excretion of faeces is very
small in fasting, it follows that the absolute quantity of nitrogen
excreted is less than with the various diets.
As regards the value of these observations it should be noted
that (according to Zaitschek, 1903, in Tangi's laboratory) the
ordinary method of determining the nitrogen of desiccated faeces
is defective, since a by no means indifferent amount of volatile
nitrogen is lost in the process of desiccation. The amount of
nitrogen which may be lost in this way varies in man from 4-7 per
cent, and may amount in the dog to 13 per cent.
These analytical researches ought, therefore, to be repeated with
samples of non-desiccated faeces, or at least the figures quoted
should be revised, since they were mostly obtained from previously
dried faeces.
352 PHYSIOLOGY CHAP.
The faeces of fasting contain a certain amount of fat, which is
probably eliminated with the intestinal secretions.
It is interesting in this connection to note that U. Lombroso
observed in some cases, after excising the pancreas in dogs, that
more fat was given off in the faeces than had been present in
the food, and again that fat was eliminated in large quantities
with a diet of egg -albumin (which contains only traces of fat).
This shows that under certain conditions the elimination of fat
by intestinal excretion may far exceed the limits generally
acknowledged.
It has further been observed that during a diet rich in fats
the faecal fat exhibits a much higher melting-point than the
alimentary fat. With a milk diet (milk-fat melts at 42°) a fat
is found in the faeces which melts at 51'5° (Miiller, Zoja).
This has been explained by a selective capacity of the intestinal
epithelium during fat absorption ; — in the sense that the epithelium
has the capacity of absorbing specific fats which vary according to
the species of animal This hypothesis, however, does not agree
with the fact that on feeding previously emaciated animals on
special fats other than that of their bodies (olive oil, mutton suet)
these are found unchanged in the adipose tissues. It is therefore
not improbable that selective activity is to be referred not so much
to absorption as to the elimination of such fatty bodies as are not
easily assimilated by the tissues of the animals of the particular
species.
The ash of the faeces during a fast does not differ in amount
from that with a normal diet. It differs in composition from the
ash of the meconium in having less sulphuric acid, chlorine, and
alkali, and more phosphoric acid and calcium. In the faeces of a
mixed normal diet these last substances are present in a higher
quantity than in fasting.
III. Hermann (1890) employed quite a different method to
determine the importance of the intestinal mucous membrane in
the formation of the faeces. He isolated a loop of intestine in the
dog, washed out its contents by a stream of disinfecting fluid,
sutured the ends to form a ring within which the substances
introduced could circulate, and then replaced it in the abdominal
cavity, which was closed up, after renewing the continuity of the
rest of the gut by a second suture.
Many animals thus operated on died after a few days from
septic peritonitis, owing to the escape of faecal matters through
the suture of the circular loop of intestine. Some dogs, however,
survived for a long time, and were killed in the 3rd-4th week after
the operation in a good state of health. Upon section, the ring
was found to be filled with a grey mass of faecal matter, which
differed from the normal faeces only in the absence of bile and of
alimentary residues. According to Hermann, this more or less
vi INTESTINE AS AN OEGAN OF EXCEETION 353
compact mass represented a concentration of the intestinal secre-
tion, which must accordingly play a prominent part in the
formation of the faeces.
Hermann's observations were much extended and varied by
his pupils Ehrenthal and Blitstein (1891), and by Berenstein
(1893). Besides employing the intestinal ring, the two first-
named caused dogs with a fistula of the gall-bladder to fast, so as
to exclude any bile from the faeces formed in the intestine. They
further made observations on the faecal masses produced in the
last part of the intestine, after establishing a preternatural anus in
the ileum, and occluding the lower end of the bowel as a cul de sac.
The whole of the digestive juices except the succus entericus are
cut off from these faeces.
The results were tolerably concordant. Both within the ring of
intestine, and in the faeces of the fasting dog with fistula of the
gall-bladder, and also in the last part of the bowel of dogs with a
preternatural anus, i.e. cut off from the digestive processes, they
found on section masses that were partly fluid, partly of a soft
consistency, composed principally of epithelial detritus with
innumerable hosts of bacteria. According to the above authors
these faecal masses must consist principally of the epithelium cells
which are continually shed from the mucous membrane, and which
mingle with the succus entericus, and are converted by bacterial
action into structureless detritus.
It is a remarkable fact that no unmistakably epithelial
structures can be recognised in the masses collected within the
intestinal ring, or in the blackish faeces formed during fasting by
dogs with, fistula of the gall-bladder. Ehrenthal ascribes this to
the fact that in the first case the bacteria (which increase
enormously within the closed ring), and in the second case the
pancreatic juice poured out into the intestine, digest the detached
epithelial cells, and convert them into formless detritus. In the
faecal masses formed in the last part of the bowel in dogs with a
preternatural anus, the microscope, on the contrary, shows not a
few well-preserved epithelial cells, perhaps because they can be
expelled by the natural anus before undergoing complete bacterial
disintegration.
Ehrenthal and Blitstein concluded from these researches as
a whole (conformably with the opinion already expressed by
Heidenhain), that the chief mass of the faeces formed under the
above experimental conditions is derived less from concentrated
secretions of the intestine than from the detached and disintegrated
epithelia of the mucous membrane.
Berenstein's subsequent work tended to correct this opinion.
He modified the method of research, experimenting with short
isolated segments of intestine, and also with the isolated Thiry-
Vella loop, and disinfected the isolated segments of the gut more
VOL. II 2 A
354 PHYSIOLOGY CHAP.
carefully, in order to restrict the action of the bacteria and cocci
which develop to such an enormous extent with the method of
the intestinal ring. Even under these conditions, in which the
intestine was not abnormally excited, he found that a slight
epithelial regeneration took place, but he concluded that a large
proportion of the excrements must under all circumstances
be formed, according to Hermann's original opinion, from the
excretory products of the intestinal mucosa.
Fritz Voit (1892) supported the same conclusion. He observed
that in a short isolated tract of intestine (35 cm. long) it was
possible in 3 weeks to obtain 14-20 grins, faeces (about O'6-l'O
grm. per diem).
We can hardly suppose that the chief part of such a large
mass can consist of shed and disintegrated epithelium. It
represents, indeed, about | the amount of epidermis and hair
which the dog (according to C. Voit) loses daily from the entire
surface of the cutis. On the other hand, this conspicuous loss of
substance from the bowel is readily explained on the assumption
that it depends essentially upon secretory processes, and that
epithelial desquamation plays a minor part.
In a careful series of new and more minute researches and
comparisons Fr. Voit confirms the fundamental facts put forward
by 0. Voit, Fr. Miiller, and Hermann, i.e. that in an ordinary diet
without excess of nitrogen, a considerable part of the faeces, and
on a flesh diet almost the whole mass, consists of the same
excretory products as are poured out in fasting, and are to a
certain extent increased with alimentation.
The larger digestive glands, i.e. the liver and the pancreas, take
hardly any part in the formation of the faeces. C. Voit in fact
found that in dogs with a fistula of the gall-bladder, the flesh or
mixed diet daily results in almost the same amount of faeces as
appeared on the same diet before the fistula was established,
showing that the bile is almost entirely reabsorbed, and takes only
a small share in the formation of the faeces.
Fr. Voit's work shows that the formation of faeces is a
physiological function almost exclusively confined to the small
intestine. On comparing the faeces formed in a short isolated
segment of intestine with those formed in the remainder of the
bowel in the same dog, he found that approximately the same
amount of faeces was obtained per unit of intestinal surface, which
leads one to suppose that not only the bile, but also the pancreatic,
gastric, and salivary secretions are for the most part reabsorbed.
The intestine, besides its digestive and absorbing functions, has
thus an excretory function, i.e. it is one of the channels by which
the waste products of the body are eliminated. That this last
function is of no little importance may be gathered from the fact
that a dog of 30 kilos, body-weight is capable, during starvation, of
vi INTESTINE AS AN OEGAN OF EXCKETION 355
forming daily 14-5 grms. faecal matter, consisting largely of
katabolites eliminated by the intestinal crypts.
Fritz Voit's results further show that the nitrogen of the faeces
formed during a moderate flesh diet comes, not from the alimentary
residues, but almost exclusively from the intestinal secretions.
The ash of the ingested flesh, on the contrary, is not completely
absorbed, and partially mixes with the faeces. Lastly, he finds
that along with the waste nitrogenous products and a moderate
quantity of salts, the isolated intestine also excretes a not in-
considerable amount of fatty substances, which constantly appear
in the faeces.
Fritz Voit also attempted to solve the problem of the absorption
and elimination of lime and iron. It is known that for adults the
quantity of lime introduced with the food is usually in excess of
what is required to maintain the calcium-balance in the body.
The question then arises as to whether the excess of lime is
absorbed or not, and if it is eliminated by the kidneys or by the
intestine.
The experiments made on dogs show that with a normal mixed
diet, particularly when rich in calcium, the greater part of the
lime salts present in the faeces come directly from the food. A
certain proportion of the calcium salts eliminated from the body
are, however, secreted in the intestinal tube, as shown by the
calcium content of the faeces in fasting. This secretion of lime in
an isolated segment of intestine increases somewhat with feeding ;
but the increment is very slight, even on a diet rich in calcium.
In this case the lime salts excreted with the urine also increase
in a moderate degree, which leads us to the conclusion that most
of the excess lime introduced is not absorbed, but mixes with, and
is eliminated in, the faeces.
As regards the absorption and elimination of iron, the results
of experiment lead us to conclude that its absorption in the
digestive canal is small ; that what is absorbed is eliminated to a
small extent by the kidneys, more by the intestine, least by the
li ver ; that, lastly, the small amount of iron eliminated with the
bile is mainly reabsorbed by the intestine.
Since little of the iron of the food is absorbed, the amount
excreted by the intestine and mixed with the faeces is also small
(a few milligrammes only). Most of the iron found in the faeces
comes directly from the food.
IV. Other interesting contributions to the theory of the
excretory function of the intestine were published from the
Institute of Hygiene at Prague by Prausnitz, Moeller, and
Kermauner (1897).
From a series of careful microscopic investigations of human
faeces during an ordinary mixed diet, Moeller concluded that,
given a perfectly healthy condition of the digestive apparatus,
356 PHYSIOLOGY CHAP.
the starch introduced with the cereals or other important vegetable
food is completely digested and absorbed.
Starch is never found in the faeces on feeding with wheat,
rye, or wholemeal bread, or with rice, potato, or pulse. It only
occurs when fresh vegetables, salad, and leguminous products
cooked whole are ingested ; or in the faeces of diarrhoea, when the
digestive apparatus is not able to perform its normal functions.
The cell-membranes, which consist of cellulose, are less digested
in proportion as they are thicker and harder: and these protect
the starch, protein, and fat from the action of the digestive juices.
The thin walls of the cell, on the contrary, can be dissolved by the
digestive juices. In any case, the amount of starch, protein, and
fat which escape the action of the digestive juices, owing to the
enclosing cellulose membrane, and are found undigested in the faeces,
is extremely small on an ordinary diet, since salad and fresh
vegetables do not usually form the staple food, but only supplement
it, cereals being ingested only after they have been ground and
converted into bread or farinaceous foods.
Kermauner studied the amount of undigested residues of meat
found in the faeces with a full flesh diet. Nearly every one agrees
that the faeces of normal individuals constantly contain more or
less modified muscle fibres, in an amount that varies with the
quantity of meat ingested. The residues of meat found in the
faeces are thus not confined to indigestible parts, such as elastic
fibres, tendon, and cartilage, but also include a certain quantity
of undigested muscle. Kermauner shows, however, that the total
amount of these substances, under normal conditions of digestion,
is always very small, and seldom exceeds 1 per cent of the meat
ingested. In an ordinary mixed diet, therefore, the non-digested
food residues are a negligible quantity. The same may practically
be stated for man, as was determined by Voit for the dog, i.e. that
in a strict flesh diet no food residues occur in the faeces, the meat
being almost entirely digested and assimilated.
From the physiological and hygienic standpoint, the chemical
investigation of human faeces methodically undertaken by Prausnitz
is more important. He attempted to ascertain the variations in
percentage composition of the content of nitrogen, ethereal extracts
(fats), and ash constituents, on different diets.
In five normal individuals (two doctors, a medical student, and
two laboratory servants) he analysed the faeces formed during an
exclusively vegetable or mainly animal diet, both represented by
foods that can be almost entirely absorbed (meat, rice, fine wheat,
bread, butter). The values obtained were then compared with the
faecal analysis of a vegetarian.
The following table sums up the results : —
vi INTESTINE AS AN OKGAN OF EXCEETION 357
No. of
Experiment.
Chief Ingredient
of Diet.
Nitrogen.
Ethereal
Extract.
Ash.
Subject.
Per cent.
Per cent.
Per cent.
1
2
Rice.
Meat.
8-83
8-75
12-43
15-96
15'37\
14-74/
1st Doctor.
3
4
Rice.
Meat.
8-37
9-16
18-23
16-04
11-05\
12-22J
Student.
5
6
Rice.
Meat.
8-59
8-48
15-89
17-52
12'58\
13-13/
2nd Doctor.
7
8
Rice.
Meat.
8-25
8-16
—
14-471
15-20J
1st Servant.
9
10
Rice.
Meat.
870
9-05
—
16'09\
15-14/
2nd Servant.
11
Rice.
8-78
18-64
12-01
Vegetarian.
As these figures show, the percentages of nitrogen, of ethereal
extract, and of ash constituents vary within narrow limits,
independent of the nature of the diet. This appears both from
the five individuals accustomed to an ordinary mixed diet, and
from the vegetarian who had been nourished for many years on
vegetable foods only (plus milk, eggs, and butter).
Seeing that in all these individuals the nitrogen content of
the faeces oscillates between 8 and 9 per cent, both on an
exclusively vegetable diet (rice and fine wheat bread) which only
contain about 1*5 per cent nitrogen, and when a comparatively
large amount of meat was added in which the percentage of
nitrogen, is much higher, we have a new argument in support of
the theory of Voit and his school, to the effect that normal
faeces consist almost exclusively of katabolic products from the
intestine.
Prausnitz gives the name of normal faeces exclusively to
those obtained on a diet of substances which can be almost com-
pletely digested and assimilated, and in which the percentage of
nitrogen fluctuates between 8 and 9 per cent. When less readily
absorbable vegetable foods are ingested, the percentage of nitrogen
in the faeces falls considerably (to 4'3 per cent), in proportion
with the amount of non- digested alimentary residues present.
In a few rare cases the percentage of nitrogen may increase, as
occurs on feeding substances which are not very absorbable, and
which contain a large amount of nitrogen.
Accordingly, the composition of the faeces is never in ratio
with that of the diet. Even on a diet which is badly digested and
ill absorbed, the faeces formed always (in consequence of the
excretion of large amounts of intestinal juice, which mixes with
the alimentary residues) contain a relatively large amount of
nitrogen in comparison with that of the food ingested. In the
apparent exceptions to this rule, the relatively low nitrogen
content of the faeces depends on the relatively high content of
358 PHYSIOLOGY CHAP.
ash constituents and other non-nitrogenous substances (ethereal
extracts).
The final conclusions arrived at by Prausnitz may be summed
up as follows : —
(a) There is no fundamental difference between plant and
animal foods as regards their utility in the human intestine.
Assimilation and absorption depend rather on their preparation
(cooking, trituration) than on their animal or vegetable origin.
(6) The foods best utilised or absorbed are those of vegetable
origin (rice, white bread or other preparations of finely ground
flour), only small traces of which are found in the faeces. With
the most profitable animal food, on the contrary, e.g. meat, un-
digested residues are always found in the faeces, although in
small quantities only. Milk and cheese give more copious faeces,
which are relatively poorer in nitrogen as compared with meat,
because they yield a larger amount of mineral residues.
(c) Human faeces, with few exceptions, consist chiefly not of
alimentary residues, but of the excretory products of the intestine.
(cT) The quantity of faeces depends principally on the nature
of the food, some kinds requiring more succus entericus for their
digestion than others. It seems, therefore, more accurate to
differentiate the foods into those which cause the production of
much or little faeces than to speak of foods which can be more or
less assimilated.
V. Stich (1853) was the first who directed attention to the
fact that faecal matters contain substances which have a toxic
action on the living body. He saw that if excreta were intro-
duced per os or per rectum from one animal into another of a
different species, more or less serious symptoms of intoxication set
in. From the fact that the toxic substances which habitually
accumulate in the alimentary canal are normally innocuous to
the animals which manufacture them, he was led to think that
each kind of animal has the power of destroying the toxins which
it produces. He assigned a predominating importance to the
protective action of the epithelium in resistance to auto-
intoxications of intestinal origin (cf. also Chapter V. § 14).
But the other facts we have discussed show that this protective
function is at any rate shared by the liver, which arrests or
converts not a few of the poisons absorbed by the roots of the
portal system.
Without entirely rejecting the protective function of the in-
testinal epithelium in Stich's sense, its excretory function, i.e. the fact
that by its means many katabolic products are eliminated from the
blood and mix with the faeces and gases of the intestine, is certainly
admitted by almost every doctor. This theory is based on a
number of suggestive observations, both clinical and experimental,
some of which attracted the attention of Bouchard. It is a fact
vi INTESTINE AS AN OEGAN OF EXCEETION 359
that persons who frequent anatomical theatres or dissecting-rooms
emit foetid faeces and effluvia which have the putrid odour of
corpses. Many physicians in ancient and modern times have
considered the intestinal catharsis by which the faeces become
diarrhoeic, either from natural causes or from the use of purgatives,
as a salutary function, i.e. an excretory process which frees the
blood from toxic waste products. " Des personnes," says Bouchard,
" qui avaient vecu pendant des annees avec la diarrhee en con-
servant les apparences d'une sante parfaite ont vu disparaitre en
meme temps leur diarrhee et leur santeY' It is certain that the
unquestionable therapeutic value of purgative waters can only be
explained on the assumption that they excite the excretory
functions of the intestine, on which the katabolic products
accumulated in the tissues and blood are rapidly expelled through
the mucous membrane of the intestine.
The toxicity of faecal extracts can easily be demonstrated by
intravenous injection. An aqueous extract of faeces injected into
the veins of a rabbit causes exhaustion, diarrhoea, and other
serious symptoms premonitory of death. An alcoholic extract is
toxic even in small doses. According to Bouchard, alcoholic
extract of 17 grins, faeces causes the death of the rabbit with
strong convulsions.
These experiments were repeated and more exactly described
by Arloing and Nicolas, with both aqueous and alcoholic faecal
extracts injected into the jugular vein of rabbits. The toxicity of
these extracts varies ; but the alcoholic is always twice as toxic
as the watery extract. The principal symptoms of intoxication
are convulsions, diarrhoea, hypothermia. Death sometimes occurs
rapidly, at other times slowly, sometimes after several days. In
the last case the animals become feverish
We do not know to what substances the toxicity of the faeces
is due. In 1882 Bouchard extracted from the faeces substances
which exhibit characters common to the alkaloids (Selmi's
ptomaines). Some of these were soluble in ether, others in alcohol.
He failed, however, to extract a sufficient quantity to produce
intoxication of the animal. In one case he succeeded in extract-
ing 15 grms. per kilo, faecal matter. He regarded the alkaloids
of the faeces as the source of all the alkaloids in the body, and
assumed a certain parallelism between the alkaloids of the faeces
and those of the urine, in which, however, they are always present
in a less amount. If these data had been confirmed they would
have been of great importance ; but later analysis carried out by
accurate technical methods gave only negative results. Selmi's
ptomaines were absent not only in normal urine and faeces, but also
in the excreta of various diseases, excepting typhus, cholera,
dysentery — diseases due to specific bacteria, which develop toxic
alkaloids as products of their metabolism.
360 PHYSIOLOGY CHAP.
Halliburton noted that clioline, one of the toxic alkaloids of
animal origin, is decomposed by the intestinal bacteria into simpler
innocuous products. He therefore thinks it probable that if other
alkaloids are normally formed in the intestine by bacterial action
they are at once broken up, like choline, by other bacteria, or even
by those which produced them.
Bouchard, in explanation of the toxicity of faecal extracts, gives
a predominating importance to the salts of ammonia and potash.
He found that on eliminating these salts from the alcoholic
extracts by means of tartaric acid, the toxicity of the latter
disappears to a very marked extent. It is also certain that the
stercobiliii formed from the bile pigments, which is soluble in
alcohol, must contribute to the toxicity of the alcoholic extracts.
Probably, however, many other waste products of the body which
are soluble in alcohol, and have not yet been chemically differ-
entiated, contribute to the toxicity of the faeces.
In fact this question, which is of great importance from the
clinical point of view, has hardly been attacked at present. Future
research must be directed towards determining not only the
chemical nature of the various substances that co-operate in the
toxicity of the faeces, but also their possible origin, i.e. whether
they are derived partly from alimentary residues, partly from the
metabolites of the body, or partly again from the toxins excreted
by the intestinal bacteria. We must confine ourselves to indicating
this possible threefold origin, without positive data as to which
of the three sources supplies most of the normal toxic products
of the faeces.
Nor can we decide how far the excretory function of the
intestine is able to replace functional insufficiency of the kidneys.
Clinically we know that diarrhoea induced by strong purgatives
can diminish the toxicity of the urine, which means that part of
the toxic waste products normally eliminated by the kidneys may
be expelled with the water discharged from the surface of the
intestine (Bouchard). The urinary constituents excreted by
the intestine do not consist mainly of urea — which is the most
important component of urine. According to Bouchard the
intestinal epithelium exerts no selective action on urea, which is
only excreted in the same proportions in which it is present in the
blood. Urea, however, is the least toxic substance of the urine,
perhaps because it has a pronounced diuretic action. To explain
the reduced toxicity of the urine after drastic purgatives, it is
therefore necessary to assume that other extractives of the blood,
which have a more toxic action than urea, may be excreted by
the intestines.
A striking clinical phenomenon in reference to this excretory
function of the intestine, as a coadjuvant and vicarious agent for
the much more pronounced action of the kidneys, is exhibited in
vi INTESTINE AS AN OEGAN OF EXCEETION 361
the prolonged oliguria and anuria which sometimes accompany
the course of those complex and uncertain forms of nerve diseases
known under the generic name of hysterical neuroses.
After two cases imperfectly described by Laycock (1838),
Charcot (1872) gave a good description of a case in which long
periods of total or quasi -total suspension of the renal func-
tions were accompanied by sickness, urea and other urinary
substances being vomited. Still more classical and important,
owing to the accessory phenomena, are two cases of hysterical
anuria described by Eossoni (1885), which may be briefly
summarised.
In a hysterical youth of 21 the periods of anuria occurred
irregularly, and differed in duration ; there were brief periods
perfectly tolerated by the body, and long periods (up to 22 days)
with slight disturbances (some headache, malaise, worry, nausea,
but complete absence of vomiting). The periods of anuria could
always be cut short by pilocarpine, which, besides considerable
sweating and flow of saliva containing urea, induced a compara-
tively abundant secretion of urine. The exhibition for experimental
purposes of 12 grms. urea during the anuria produced an uraemic
attack, which gave way to the subcutaneous injection of 0'02 grm.
pilocarpine hydrochlorate. During the disease the diet was very
scanty, with little nitrogenous food (fruit, dressed vegetables,
farinaceous preparations). The patient was kept altogether in
bed with complete rest. There was constant constipation from
intestinal paresis. The faeces were removed every two or three
days by enemata, in amounts varying from 150 to 250 grms. (No
chemical examination was made of the faeces.) For twelve days
there was acute fever (from 38'8° to 40-I7° C.), after which it
subsided ; but the temperature for months was above 38° C.
After about 8 years this patient was suddenly, so to speak
" miraculously," cured of all hysterical phenomena, including the
periods of anuria or oliguria, in consequence of a strong joyful
emotion.
Another youth of 18 became hysterical after a sudden psychical
shock. Violent convulsive attacks, with obstinate nasal and
gastric haemorrhage, were followed by ischuria, which in turn was
succeeded by irregular periods of oliguria and complete anuria,
usually accompanied by vomiting of a fluid which had all the
physical and chemical properties of normal human urine. At
other times, however, the period of anuria ran its course without
grave symptoms (headache, peripheral disturbances of circulation,
slight tremor of extremities), and without vomiting as a substitute
for the suspended functions of the kidneys. During the illness
there was an interval of 50-60 days, in which the periods of total
anuria were not accompanied by vomiting. In this patient the
administration of pilocarpine during anuria produced sweating and
362 PHYSIOLOGY CHAP.
salivation, but never started the urinary secretion as in the first
hysteric. Hypodermic injection of 15 grins, urea, during absence
of vomiting and persistent anuria, produced a violent attack of
convulsions with subsequent tetany and coma, which gradually
gave way under a flow of saliva containing urea and sweating
promoted by pilocarpine. On the other hand, an injection of 14
grms. urea during a period in which abundant vomiting accom-
panied the anuria produced no disturbance. The daily diet was
restricted, and the patient was kept entirely in bed.
Since the tendency of hysterical patients to simulate extra-
ordinary phenomena is well known, Kossoni (in order to obtain an
unexceptionable proof of the long periods of total anuria) requested
the surgeon Crespi to perform a perfect ureterorrhaphy during a
period of anuria. After seven days there was complete cicatrisa-
tion, with perfect occlusion of the urethral ineatus. On the 20th
day after the operation, since the patient did not complain of any
particular trouble, the urethra was reopened in presence of several
well-known Roman doctors, and it was shown by means of a
catheter that the bladder did not contain a single drop of urine. A
large rubber syringe was kept permanently in the bladder for 10
more days, during the whole of which time it was not possible to
obtain any urinary secretion.
These two clinical cases have a double interest for physiologists:
(a) because they afford a new objective proof of the excretory
function of the entire gastro-intestinal system with its glands, as
a substitute for the normally more important function of the
kidneys ; (&) because they demonstrate the astonishing fact of a
total and prolonged suspension of the renal secretion owing to
simple nervous causes.
Leaving to Chapter VIII. the critical examination of the second
phenomenon (which is certainly the most important) we will here
confine ourselves to the first point.
To begin with, we must note with Eossoni that clinical
observation does not confirm Charcot's statement that prolong
anuria, as observed at irregular periods in hysterical subjec
must be accompanied by urinous vomiting in order to avert
uraeniic attacks, and to be compatible with life without grave
functional disturbances. In the first case vomiting never occurred
during the repeated and prolonged attacks of anuria; in the
second there were periods of anuria with vomiting and urinous
salivation, which were evidently substitutive for the function of
the kidneys, but long periods of anuria without vomiting and
with mild disturbances were not wanting. When the anuria is
accompanied by vomiting, the entire gastro-intestinal canal with
its glands (the salivary glands included) takes an active part in
the vicarious excretory function ; but when vomiting is absen
we must logically conclude that the lapse of acute urae
vi INTESTINE AS AN OKG-AN OF EXCEETION 363
symptoms during the anuria is more particularly due to the
vicarious action of the entire intestinal tract. Although
direct evidence for this is wanting (since the faeces were not
examined chemically for urinous products) it seems from the
physiological point of view to be incontestable. Eossoni, to
account for the absence of acute uraemic phenomena during the
anuria without vomiting, invokes the extreme slowness of meta-
bolism in the two hysterical patients. There is not, however, the
slightest proof of this, and even if it were proved, it would at
most explain the oliguria and not the prolonged periods of total
anuria.
Kossoni's statement, that injections of pilocarpine were always
able in the first subject to interrupt the anuria by reactivating
the renal function and improving the general state of the patient,
while in the second they only promoted the vicarious functions
of the skin and salivary glands, is interesting. But according to
what we stated in Chapter IV., the pilocarpine, both in the first
and the second subject, must have activated the secretion of all the
glands connected with the gastro-intestinal canal, particularly the
liver and the crypts of Lieberklihn, from which it is probable that
the most highly toxic products poured out into the blood from the
tissues were eliminated by the intestine, during the total suspen-
sion of renal secretion.
Since the innocuous character of injections of urea, when the
kidneys are functioning normally, is well known (Chapter VII.,
pp. 411, 413), the fact which Kossoni observed is very interesting,
i.e. that the administration of 12 grms. urea during anuria caused
a uraemic attack, due no doubt to a sudden rise in the osmotic
pressure of the blood. In the second hysterical patient, hypo-
dermic injection of 15 grms. urea during the anuria without
vomiting produced the same effect, while a second dose of 14
grms. urea was tolerated without toxic symptoms, because it was
given during the anuria accompanied by abundant urinous vomit-
ing, i.e. when the patient was urinating not by the kidneys, but
by the stomach.
VI. The complex task of the intestinal apparatus, as expressed
in the triple function of digestion, absorption, and excretion or
formation of faeces, ends with the mechanical process of defaeca-
tion. It is generally assumed for man that the intestinal chyme
remains in the majority of cases for about 4 hours in the small
intestine, and about 22 hours in the large bowel (Nothnagel).
The peristaltic movements which drive it onwards become pro-
gressively slower in proportion as it descends into the lower parts
of the small intestine. Along with this delay there is a constantly
increasing condensation of the intestinal contents, in consequence
of the absorption of water, and of the absorbable constituents of
the chyme. In proportion as the contents of the intestine assume
364
CHAP.
a firmer consistency, their colour, odour, and external characters
approximate to those of the faeces.
On reaching the lower end of the ileum, the substances which
have accumulated and escaped absorption, are forced on by the
peristaltic movements through the cleft of the ileocaecal valve,
and pass into the large bowel. The lips of this cleft lie trans-
verse to the caecum, and are so arranged that the distension of
3V'-
Fio. 102.— The caecum in connection with the ileum and colon. (Luciani.) The anterior exter
wall of the caecum has been cut away to show the cleft and labra of the ileo-caecal valve, wi
the orifice of the vermiform appendix, ci, fundns of caecum ; av, vermiform appendix ; o
its opening into the cavity of the caecum ; iZ, last tract of ileum ; v and v", lower and upp
labra, which circumscribe the cleft of the ileo-caecal valve ; co and co', first and second segme
of ascending colon.
the caecum brings them together in the position of closu
(Fig. 102). The watertight closure of the ileocaecal valve
comes still more perfect when the peristaltic movements of
large intestine begin in the fundus of the caecum. The conten
of the caecum is then voided into the colon without any possibilit
of reflux of faecal matter into the ileum, because the increase o
intracaecal pressure applies the lips of the valve still more firml;
together. This passage of the excreta from the small into t"
large intestine has been regarded by some (Viault and Jolyet)
a first, internal defaecation, in which the faeces, freed from
useful constituents (like the exhausted residues on a filter)
vi INTESTINE AS AN OEGAN OF EXCEETION 365
from the digesting part of the intestine into the large bowel,
which acts as a sort of reservoir, while the valves hinder any
reflux that might disturb the digestive processes still going on
throughout the small intestine. However acceptable this theory
may be from the mechanical point of view, it is less valid for the
chemist. The digestive processes effected by the juices with
which the faeces are saturated can go on in the large intestine
also. In fact, the fermentative and putrefactive processes set up
by the intestinal bacteria are continued, and even reach their
maximal development, in the large bowel. For while the con-
tents of the ileum are slightly alkaline, neutral, or faintly acid,
the reaction of the large intestine in carnivora, and in man, is
always decidedly acid. This depends not on any acid property of
the secretion of the mucous membrane of the large bowel, but
upon the acid fermentation developed in its contents, as proved
by the development of methane and hydrogen which, as we have
seen, is conspicuous in the large intestine. We know, on the
other hand, that although the large intestine is provided along its
entire length, from the vermiform appendix to the anus, with
innumerable crypts (see Fig. 44, p. 125) its secretion is alkaline,
and rich in mucin, with no constituent capable of acting chemi-
cally upon the three main groups of food-stuffs. All the chemical
changes in the large intestine (with the exception of such as may
be due to the enzymes from the small intestine, before the acidity
of the medium arrests their activity) must therefore be caused by
the intestinal bacteria.
In all probability the chemical changes that take place in the
large intestine are unimportant in the carnivora and in man, but
they have an enormous importance in the herbivorous rodents,
and for solipeds, in which the caecum is much larger than the
stomach. The contents of the caecum in the horse and in
ruminants, unlike those of the carnivora and of man, are always
very abundant ; not acid, as stated by Tiedemann, Gmelin, and
others, but always decidedly alkaline, even (according to numerous
observations of Colin) more strongly alkaline than the contents of
the different parts of the small intestine and the entire colon,
where the reaction becomes gradually acid owing to the fermenta-
tion which gives rise to formation of lactic, butyric, and other
fatty acids. According to Colin, the alkaline fluid which saturates
the contents of the caecum is derived principally from the mixture
of digestive secretions poured out into the small intestine, and
only to a minimal extent from the mucous secretion of the crypts
of the caecum. Since the incompletely digested food-stuffs remain
for a long time in the caecum, it is evident that the digestive
processes initiated in the small intestine must be continued there.
Colin's logical conclusion was experimentally confirmed by
Paladino (1875), who demonstrated in a series of researches into
366 PHYSIOLOGY CHAP.
the caecal digestion of the horse, that the fluid collected from the
caecum of this animal exerted a marked digestive action on food-
stuffs (starch, proteins, oats, vegetables) either in vitro, or when
introduced into the cavity of the caecum through an artificial
anus (at the point of the caecum) by the help of which the
successive changes could be examined.
Ellenberger and Hofmeister (1881) confirmed the alkalinity of
the caecal juice and its capacity of digesting both starch and
cellulose, with evolution of gas. They also found a small quantity
of peptone in the contents of the caecum, while none was present
in the colon or rectum. It is probable that part at least of this
peptone is formed in situ, and that the caecal juice has also the
power of digesting protein.
It was, however, shown by Bergman and Hultgren (1903) that
the caecum was not a vital organ even in herbivora. After
cutting out the whole of the caecal tract from the remainder of
the intestine in adult rabbits, they made quantitative investiga-
tions of alimentary absorption, as compared with what took place
in normal, control animals. Although they came to no definite
conclusion as to the importance of the caecum in the digestion
and absorption of cellulose, their researches indicate that the
capacity for assimilating other food-stuffs was unaltered. Nothing
abnormal was noted in rabbits deprived of their caecum, except a
diminished capacity for ingesting large quantities of food, which
did not, however, interfere with their general health.
Apart from the digestive processes carried on in the caecum of
herbivora by means almost exclusively of the juices secreted in
the small intestine, it is certain that the principal function of the
caecum (and, generally speaking, of the whole large intestine) is,
not only in these animals but also in carnivora and in man, to act
as a reservoir for the faecal masses, so that a large part of the
water and nutrient matters which they contain may be absorbed
and utilised.
This fact was especially brought out by the work of Marcacci
(1888). He tied or excised the caecum in various animals (dogs,
rabbits, sheep, fowls), after which he observed disorders of defaeca-
tion with emission of liquid faeces, containing dextrose and some-
times a trace of peptones, when the animals were allowed as much
water as they pleased with their food.
Berlatzky (1902) established a fistula of the caecum in dogs,
separating it from the large intestine and uniting its orifice with
the abdominal walls. He saw % that a minimal secretion took place
during fasting, which increased considerably after ingestion of
food. The quality of the food had no influence on the amount
of secretion. The caecal juice was strongly alkaline, partly
fluid and partly slimy. It was incapable of digesting either
fibrin or egg-albumin, and failed to activate other enzymes
vi INTESTINE AS AN OEGAN OF EXCEETION 367
(enterokinase). It did, however, contain an amylolytic ferment
and Cohnheini's erepsin.
While nothing definite is known, we are justified in assuming
that along with digestive functions, the fermentation and putre-
faction of substances accumulated in the large intestine, and the
absorption of water and of certain soluble products, the large
intestine also excretes the waste products of the body, which
mingle with its contents, and increase the mass of the faeces.
From these products we must distinguish the mucus, which is by
a long way the chief constituent of the secretion from the epi-
thelial cells of the large intestine, both of the superficial cells and of
those which line the numerous crypts. This mucous secretion has,
as we showed elsewhere, the specific function of lubricating the
external surface of the faecal balls, so as to facilitate their
expulsion by the anus.
In proportion as the faecal masses are condensed by the active
absorption that takes place in the large bowel, and assume a
pasty, or more or less hard, consistency, absorption of the toxic
substances contained in the faeces becomes more and more
difficult. The phenomena of auto-intoxication are thus avoided,
because under normal conditions the toxic constituents of the
faeces are so slowly absorbed, that they are eliminated by the
urine as fast as absorption takes place. As soon, therefore, as
the faeces have attained a proper consistency, absorption ceases
entirely, and the toxic matters are expelled with the faeces in
defaecation (Bouchard).
VII. In man the Large Intestine with its three parts (caecum,
colon, rectum) is I'SO-l'SO m. long, i.e. about one-fifth of the whole
length of the intestinal canal. Its diameter is greater than that
of the small intestine, and varies in the different parts from 5 to
12'5 cm. The caecum has the largest diameter, which diminishes
gradually in the three segments of the colon (ascending, transverse,
sigmoid), and in the rectum, except that near the end of the latter
there is a well-marked dilatation (rectal ampulla'). Like the
stomach and small intestine, it has four coats (serous, muscular,
submucous, and mucous), but the greater part of the large intestine
(caecum, colon) differs very much from the even, cylindrical form
of the small intestine, its surface being thrown into numerous
sacculi. This comes from the arrangement of the longitudinal
muscle fibres, which thicken in the form of three strong bands
(sometimes known as the ligamenta coli) and are shorter than the
part of the tube through which they run, so that it exhibits three
series of saccular dilatations, separated by constrictions ; these
correspond inside the gut with three more or less prominent
ridges composed of all the coats, by which the canal is thrown
into sacculi (Fig. 103). This arrangement is certainly intended
to delay the advance of the faecal mass along the large intestine,
368
PHYSIOLOGY
CHAP.
and to favour absorption of the soluble substances and concentra-
tion of the faeces. Another peculiar feature of the large intestine
is the so-called appendices epiploicae, which, however, are of little
physiological importance.
In the rectum the longitudinal muscle fibres are reduced to
two bundles, one anterior, the other posterior. They do not give
rise to any formation of ridges and sacculi. In the rectal ampulla
the mucous coat alone exhibits longitudinal folds, which are
FIG. 103. — (Left.) Outline sketch of a section of the ascending colon. (Allen Thomson.) s,
serous covering ; s1, s', reflection of this at attached border forming a short wide mesocolon
between the folds of which the blood-vessels are seen passing to the colon ; a, one of the
appendices epiploicae hanging from the inner border ; lm, indicates at free border one of the
three bands formed by the thickening of the longitudinal muscular coat ; the dotted line
continued from the margins of these bands represents the remainder of the longitudinal
muscular coat, and the thick line within it, marked cm, represents the circular muscular
layer ; m, the mucous membrane at the flattened part ; r, the crescentic bands of indentations
which divide the sacculi.
Fio. 104. — (Right.) Diagram of last part of rectum, with the sphincters and muscles of the anal
region. (Testut) R, rectum ; f.c, circular coat ; f.l, longitudinal coat ; Si, internal sphincter
of plain muscle ; S.e, external sphincter of striated muscle ; m.e, levator ani ; m.o.i, obturatoriu
internus ; /, os ischiadicum.
obliterated when it is distended by the faecal masses. At the
level of the anal canal, the longitudinal fibres completely surround
the rectum, and the circular fibres thicken and form the so-called
internal sphincter. At the end of this layer of plain muscle a
firm ring of striated muscle forms the external sphincter. Beyond
this last is another striated muscle, the levator ani, which forr
a sort of diaphragm, the concavity being turned upward anc
forward (Fig. 104).
With these anatomical premises, it is easy to understand the
mechanism of defaecation, which, as distinguished from that
which takes place through the ileocaecal valve, may be termed
vi INTESTINE AS AN OEGAN OF EXCEETION 369
external defaecation. It is preceded by peristaltic movements of
the muscles of the large bowel, which differ from those of the
small in being slower and less vigorous, the muscles of the large
intestine being comparatively scanty in comparison with the
diameter of the canal, which far exceeds that of the small intestine.
The three longitudinal bands must shorten the canal in contract-
ing, and compress the sacculi, thus facilitating the propulsion of
the faecal masses from one saccule to another. While one of
these empties itself by the combined contraction of the circular
and the longitudinal fibres, the next dilates by the relaxation of
its muscles, and fills with the faecal masses expelled from the
preceding.
The mechanism of the movements of the large intestine corre-
sponds on the whole with that of the small intestine, as shown by
Bayliss and Starling (1900-1), who extended their earlier work
(see p. 240 et seq.^) on the small to the large bowel. But while
antiperistaltic movements are, as we have seen, the exception
in the small intestine, Cannon's experiments (1901) with the
Rontgen rays show that they occur normally in the large bowel.
The peristalsis of the large bowel is not a continuation of that
of the small ; while the latter ceases at the ileocaecal valve, the
former commences at the fundus of the caecum and extends from
•the caecum to the colon, till it reaches the end of the sigmoid
flexure, where the faeces are supported by the bladder and sacrum.
O'Beirne of Dublin (1833) was the first to state on the strength
of numerous observations that under normal conditions, i.e. when
they attain a certain degree of consistency, the faeces remain in
the sigmoid colon, and do not descend into the rectum during the
interval between one evacuation and the next. It is a fact that
on digital exploration of the rectum, even at the moment that
precedes evacuation, i.e. when the subject feels the need to
defaecate, the rectal ampulla is empty, and the exploring finger is
seldom smirched. Even after an operation for anal fistula in which
the sphincters are divided, the patient can usually retain the
faeces during the interval between two evacuations. These ob-
servations show that the faeces normally stay in the sigmoid colon,
supported by the bladder and sacrum, and only descend into the
rectum when the excessive accumulation of the faeces, and the
pressure these exert upon the walls of the colon, arouse the need
of defaecating, and reflexly exaggerate the peristaltic movements
of the large bowel.
After the faecal mass has descended into the rectum, the
mechanical excitation of its sensory nerves still further increases
the desire to defaecate.
Defaecation can be inhibited for a certain time by voluntary
contraction of the external sphincter and the levator ani. By
this mechanism it is sometimes possible to postpone the act for
VOL. II 2 B
370
PHYSIOLOGY
CHAP.
a while, probably because the faeces which have descended into
the rectum are partly pushed back into the colon by the action of
these muscles. But when the tension of the walls of the colon
and rectum exceeds certain limits, this voluntary mechanism not
only fails to remove the sensation of desire but even increases it,
by reflexly promoting the active movements of the lower part of
the rectum, which makes the need to defaecate more urgent, and
aids evacuation where it is sluggish.
A spurious desire to defaecate may be aroused by pressure
exerted ab extrinseco on the walls of the rectum from a large
calculus in the bladder,
a tumour of the prostate,
or the presence of the
head of the foetus in the
pelvis. The same effect
may be produced by in-
ternal haemorrhoids, or
an inflammation of the
rectal mucosa such as
is commonly associated
with dysentery. The
term tenesmus is em-
ployed in medicine for
this spurious desire to
evacuate.
Three mechanical
factors normally co-
operate in the act of
FIG. 105.— Schema of dog's hypogastric plexus, with afferent j « , • , -, ,-
nerves, and efferent nerves to rectum, anus, and bladder. QeiaecailOn : (Ci) active
(Frangois-Franck.) G.m.i, inferior mesenteric ganglion ; -i-variaf-ciloiQ
N.c, nervous erigens from 1 and 2 sacral nerves (IS, SS) ; Jr31
N. pud.int, nervous pudendus internus ; P.i, hypogastric
plexus,-which with the nervous pudendus innervates the
rectum, anus, and bladder.
the
of the sigmoid colon anc
rectum ; (6) inhibition of
the tone of the sphincter
aided by the contraction of the levator ani ; (c) active inter ventioi
of abdominal compression, by contraction of the diaphragm anc
forcible and prolonged contraction of the abdominal muscles witl
closure of the glottis. The association, succession, and co-ordination
of these factors varies in different cases, according as there is
tendency to diarrhoea or to constipation.
It is certain that of the three mechanical factors which thi
take part in the act of defaecation, the first is the most essenti*
In fact (as we shall see), under certain experimental or pathologic
conditions the entire process of evacuation may take place as
pure reflex, independent of any active intervention of the voluntary
muscles.
VIII. The nerves of the large, like those of the smai
intestine come from the cerebrospinal and from the sympathetic
vi INTESTINE AS AN OKGAN OF EXCEETION 371
-5.L
system. The former are branches of the lumbar and sacral nerves,
the latter of the inferior mesenteric plexus and the hypogastric
plexus (see Fig. 83, p. 247). The sensory fibres from this last
plexus cause the excessive sensibility of the mucous membrane of
the rectum and anus, and its motor fibres discharge the movements
of defaecation. The hypogastric rami from the lumbar cord run in
the same plexus after traversing the inferior mesenteric plexus,
along with the fibres from the
anterior roots of the first and
second sacral nerves, which under
the name of the nervus erigens
(Eckhard) innervate the corpora
cavernosa, and give off the nervus
pudendus, from which the haemor-
rhoidal rami run to the sphincters
of the anus (Figs. 105 and 106).
The closure of the ileocaecal
valve is also effected by nervous
action (Katz and Winkler, 1902).
Stimulation of the central end of
the sciatic relaxes the closed valve,
or brings it to, if previously open.
Stimulation of the vagus usually
produces closure of the splanchnic
opening. The nervi erigentes and
the hypogastrics are ineffective, so
that its innervation again shows
the ileocaecal valve to belong to the
small intestine.
The question already discussed
in Chapter IV. (p. 265 et seq.) as to
the simultaneous or alternate action
of the longitudinal or circular
fibres of the small intestine, comes
up again in relation to the
muscles of the colon and rectum.
Certain experimenters (Courtade
and Guyon, 1897) stated that electrical stimulation of the
sympathetic rami in the dog produces contraction of the circular
fibres of the colon, rectum, and anus, and inhibits the contraction
of the longitudinal fibres ; vice versa, stimulation of the sacral
nerves contracts the longitudinal and inhibits the circular fibres,
including those of the sphincter. There would thus be a functional
antagonism between the two orders of nerves. On the other
hand, Langley and Anderson (1895-96), experimenting on the
rabbit, state that stimulation of the sacral nerves throws both
longitudinal and circular muscles into contraction, while stimula-
Fia. 10(5. — Schema of nerves which arise (in
dog) from last part of lumbar cord, and
in sacral cord. (FranQois-Franck.) Sa,
os sacrum ; BL, GL, 7L, lumbar vertebrae ;
N.sc, sciatic nerve ; N. e, nervous erigens
from 1 and 2 sacral nerves (IS, %S) ; N. p,
nervous pudendus ; C. e, cauda equina.
372 PHYSIOLOGY CHAP.
tion of the sympathetic rami sometimes produces a brief contraction,
but as its principal effect causes inhibition of all the movements
of the last part of the gut. The action of the sacral and sympa-
thetic fibres on the colon, rectum, and anus would thus be analogous
to that exerted by the vagus and splanchnics on the rest of the
stomach and intestines. It is an open question, left for further
investigation to decide.
The tonic contraction habitual to the sphincters of the anus is
due, in part at least, to the action of a nervous centre situated in
the lumbar segment of the cord. According to Budge and Masius
(1868) this ano-spinal centre is localised in dogs in the tract
corresponding with the level of the fifth lumbar vertebra, in
rabbits, on the other hand, in the tract between the sixth and
seventh lumbar vertebrae. If in these animals the cord be
divided below the ano-spinal centre, or if in rabbits the abdominal
aorta be compressed for a long period (Gaglio), relaxation of the
sphincters follows. If, on the contrary, the cord be cut above
the level of this centre, the sphincters regain their normal
tonicity as soon as the inhibitory effect of the operation has
passed off.
More recently, however, Goltz and Ewald (1895) observed
in dogs deprived of the whole of the lumbar-sacral cord that the
phenomenon of incontinence of faeces disappears after some months,
and the anal sphincters regain their normal function. The sympa-
thetic ganglia can thus regulate the tone of the sphincters inde-
pendently of the ano-spinal centre. In fact, after the destruction
of the spinal centre, Courtade and Guyon (1897), and subsequently
Frankl-Hochwart (1900), saw that centripetal excitation of the
hypogastric rami, which give off sensory fibres to the ano-rectal
mucous membrane, can produce reflex contraction of the sphincters.
The reflex ceases after destruction of the inferior mesenteric
plexus. The central station of the reflex therefore lies in thi«
plexus, since all relation of the latter with the spinal centre
previously been abolished.
The sphincters are also capable, after some months, of regaining
their natural tone, when the whole of the nerves that supply the
rectum and the anal sphincters have been completely occluded,
along with the central action of all the extra-rectal sympathetic
ganglia. This was established for dogs by Arloing and Chanti
(1897-98) by repeated experiments. This fact can only be explaine
by admitting that the intra-rectal peripheral ganglia of Auerbach's
plexus can exercise a reflex tonic action upon the sphinctei
independent of the connections with the extra-intestinal nervoi
system.
We must therefore conclude that in cases of incontinence of
faeces of central origin there is, along with the depression of the
tonic action of the ano-spinal centre, also a functional inhibition
vi INTESTINE AS AN OKGAN OF EXCKETION 373
of the ganglia of the inferior rnesenteric plexus, and the intra-
rectal peripheral ganglia.
Another interesting phenomenon first observed by Gluge(1868)
on the rabbit, and subsequently noted by Goltz (1874) on the dog,
and by Ott (1879) on the cat, appears to show that the tonic
action normally exerted on the anal sphincters by the ano-spinal
centre depends in its turn upon an influence transmitted to this
same centre from the brain. In these animals, after dividing the
cord between the last dorsal and the first lumbar vertebrae, it is
seen, both with digital exploration of the anus and by the graphic
method, that the sphincters have lost their tonic contraction, and
exhibit rhythmical contractions instead. Goltz counted 20-25 per
minute in the dog. They may arise spontaneously, or may be
provoked by stimulation of the anal muscles, or inhibited by
excitation of the sensory nerves of the lower limbs. Ott recorded
Fit:. 107. — Rhythmic contractions of anal sphincter (in cat), after transverse division of lumbar
cord, recorded by rectal sound. (Ott.) a, stimulation of sciatic : arrest of sphincter-beats ;
6, end of stimulation : return of beats which are more vigorous and irregular.
the same phenomenon on the cat with the graphic method (Fig.
107). After ablation of the lower part of the cord, or division of
the anal nerves, these rhythmic movements of the sphincters are
abolished (Chauveau, Arloing), but after a few weeks or months
they may appear again. Goltz and Ewald in fact observed this
phenomenon in a dog that had undergone almost complete
ablation of the spinal cord two years previously.
Many observers have shown that the brain exerts an influence
upon the ano-spinal centre and the homologous sympathetic
centres, by transforming the rhythmic contractions of the
sphincters (which they excite) into a tonic contraction. After
stimulating the base of the crura cerebri a spastic constriction of
the anus is readily seen, along with other diffuse movements. On
cutting the optic thalamus of the cat, Ott (1879) saw rhythmic
movements of the anus. Sherrington (1902), in a more exact
experiment, found that an induced current applied to the posterior
portion of the paracentral lobe in the ape produced spasm of the
anal sphincters. Mayer (1893) observed similar effects in the dog,
on stimulating the posterior part of the sigmoid gyrus near its
374 PHYSIOLOGY CHAP.
outer border. Mann (1895) in the cat and rabbit, on stimulating
certain points of the motor cortex, obtained co-ordinated movements
of defaecation. Ducceschi (1898), in dogs deprived of the motor
cortex, observed rhythmic contractions of the anus entirely com-
parable to what is seen after section of the lumbar medulla. This
is not seen in dogs after removal of the cortex of the frontal or
occipital lobes. On stimulating the superior and anterior margin
of the precruciate convolution of the sigmoid gyrus with an induced
current he obtained contractions of the anus, associated sometimes
with movements of the tail.
On the strength of these facts we may conclude that there is an
ano-cortical motor centre, which controls the function of the ano-
spinal centre. It is this centre that puts into voluntary motion
the external sphincter of the anus and the levator ani, either to
retard the act of defaecation, or to promote it, by increasing the
intra-rectal tension and reflexly determining a more energetic
peristalsis of the sigmoid flexure and rectum. Inhibition or
temporary paralysis of this centre (e.g. from fright) may produce
involuntary evacuation.
The whole act of defaecation may take place periodically,
independent of the cortical centres, by a pure reflex act, regulated
by the lower spinal or sympathetic centres. This was particularly
observed by Goltz, both in dogs with divided cord and in those
deprived of the lower part of the cord.
These reflex actions are determined by the distension of the
last part of the intestine due to accumulation of faeces, which
excites the sensory nerves of the mucosa. Diminished excitability
of these sensory nerves or the centres with which they are in
relation is probably the cause of habitual costiveness and obstinate
constipation.
Deficient oxidation of the blood circulating in the walls of the
last part of the intestine, again, or a sudden arrest of the vascular
circulation, may reflexly produce powerful peristaltic movements
which expel the faeces, independent of voluntary control. This
explains the defaecation frequently seen in cases of sudden death
from asphyxia or suffocation, as well as the exaggeration of
intestinal peristalsis observed on opening the abdomen of animals
immediately after death (Foster).
In conclusion there are certain specific functional characteristics
by which the external sphincter of the anus is differentiated from
all other striated muscles.
We have seen that when completely withdrawn from the
influence of the cerebrospinal nerve centres, it regains its normal
tonicity after some months, does not atrophy, nor undergo fibrous
degeneration, and preserves its normal excitability to electrical
stimuli (Goltz). It must further be added that, even under
normal conditions, the external sphincter differs from the other
vi INTESTINE AS AN OKGAN OF EXCKETION 375
striated muscles in the special form of its contraction curve, which
is slower in all its phases, resembling that of plain muscle
(Ducceschi). Lastly, the external sphincter, shortly after destruc-
tion of the cord, becomes insensitive to the paralysing action of
curare (Goltz), or at any rate much larger doses of curare are
required to paralyse it than are necessary for other skeletal muscles
(Frankl-Hochwart and Frohlich).
From the later work of these authors (1900) we may also
conclude : (a) that the internal sphincter alone (excluding the
co-operation of the external sphincter) is able to ensure the tonic
closure of the anal orifice ; (&) that curare has no visible effect on
the tone of the internal sphincter ; (c) that the external sphincter
is responsible for 30-60 per cent of the total energy with which
the tonic closure of the anal orifice is normally maintained ; (cT)
that the nervi erigentes (Eckhard) contain fibres which on
excitation produce contraction of the external sphincter ; (e) that
excitation of the hypogastric rami with previous division of the
nervi erigentes usually (9 out of 12 times) determines the dilatation
of the sphincters ; (/) that stimulation of the sciatic excites reflex
contraction of the sphincter, and dilates it reflexly after section of
the nervi erigentes.
BIBLIOGRAPHY »
Composition and Origin of Faeces : —
C. VOIT. Hermann's Handbuch der Phys. vi. Part I.
FR. MULLER. Zeitschrift f. Biol. xx., 1884.
RIEDER. Ibidem.
ROSSONI. Rivista clinica di Bologna, October 1885.
LUCIANI. Fisiologia del digiuno. Studi sull' uomo. Florence, 1889.
HERMANN. Pfliiger's Arcli. xlvi., 1890.
EHRENTHAL and BLITSTEIN. Ibidem, xlviii., 1891.
FRITZ VOIT. Zeitschr. f. Biol. xxix,, 1892.
BERENSTEIN. Pfliiger's Arch, liii., 1893.
C. LEHMANN, FR. MULLER, I. MUNK, SENATOR, ZUNTZ. Untersuclmngen an zwei
hungernden Menschen. Berlin, 1893.
HAMMERL, KERMAUNER, MOELLER, and PRAUSNITZ. Zeitschr. f. Biol. xxxv., 1897.
C. CORLETTE. Journal of Physiology, xxv., 1900.
ZAITSCHEK. Pfliiger's Aroh. xcviii., 1903.
Toxicity of Faeces : —
BOUCHARD. Le9ons sur les auto-intoxications. Paris, 1887.
Functions of Caecum : —
COLIN. Traite de phys. comp. des animaux. Paris, 1871.
PALADINO. Sulla digestione cecale nei grandi erbivori. Naples, 1875.
ELLENBERGER and HOFMEISTER. Arch. f. wiss. u. prakt. Thierheilk. v., x., xi.,
1881-83.
A. MARCACCI. II significato fisiologico dell' intestine cieco. Perugia, 1888.
BERGMAN and HULTGREN. Skand. Arch. f. Physiol., xiv., 1903.
Mechanism and Innervation of Movements of Large Intestine and of Defaecation :
MASIUS. Bull, de 1'Acad. Roy. de Belgique, 1867-68.
GLUGE. Bull, de 1'Acad. R. de Belgique, 1868.
GOLTZ. Pfliiger's Arch, vi., 1873.
376 PHYSIOLOGY CHAP, vi
OTT. Journ. of Physiol. ii., 1879-80.
GOLTZ and EWALD. Pfliiger's Arch. Ixiii., 1890.
SHERRINGTON. Centralbl. f. Physiol. vi., 1892.
MEYER. Neurol. Centralbl. xii., 1893.
MANN. Journ. of Anat. and Physiol. xxx., 1895.
LANGLEY and ANDERSON. Journ. of Physiol. xviii.-xix., 1895-96.
DUCCESCHI. Rivist. di pat. nerv. c ment. iii., 1898.
ARLOING and CHANTRE. Com p. r. de 1'Acad. des Sc., 1897-98.
COURTADE and GUYON. Journ. de phys. et de path, gen., 1889.
FRANKL-HOCKWART and FROHLICH. Pfliiger's Arch. Ixxxi., 1900.
BAYLISS and STARLING. Journal of Physiol. xxvi., 1900-1.
KATZ and WINCKLER. Beitr. z. exp. Pathol., 1902.
Recent English Literature : —
C. CORLETTE. An Experimental Research on Excretion in the Small Intestine.
Journal of Physiol., 1899-1900, xxv. 344.
W. H. PARKER. The Occurrence and Origin of the Xanthine Bases in the Faeces.
Amer. Journ. of Physiol., 1901, iv. 83.
C. A. HERTER and H. C. WARD. On Gas Production by Faecal Bacteria grown on
Sugar Bouillon. Journ. of'Biol. Chem., 1905-6, i. 415.
C. A. HERTER. The Production of Methyl Mercaptan by Faecal Bacteria grown
on a Peptone Bouillon. Journ. of Biol. Chem., 1905-6, i. 421.
J. A. FRIES. Intestinal Gases of Man. Amer. Journ. of Physiol., 1906, xv. 468.
A. E. BOYCOTT and G. C. C. DAMANT. A Note on the Quantities of Marsh Gas,
Hydrogen and Carbon Dioxide produced in the Alimentary Canal of Goats.
Journ. of Physiol., 1907-8, xxxvi. 283.
C. A. HERTER. The Occurrence of Skatol in the Human Intestine. Journ. of
Biol. Chem., 1908, iv. 101.
CH. DOREE and J. A. GARDNER. The Origin and Destiny of Cholesterol in the
Animal Organism. Part I. On the So-called Hippocoprosterol.
CH. DOREE and J. A. GARDNER. Part II. The Excretion of Cholesterol by the
Dog. Proc. Roy. Soc. of London, 1908, Ixxx. 212 and 227.
0. FOLIN and A. H. WENTWORTH. A New Method for the Determination of Fat
and Fatty Acids in Faeces. Journ. of Biol. Chem., 1909-10, vii. 421.
C. A. HERTER and A. J. KENDALL. The Influence of Dietary Alternations on the
Types of Intestinal Flora. Journ. of Biol. Chem., 1909-10, vii. 203.
CHAPTEE VII
ORIGIN OF KATABOLIC CONSTITUENTS OF URINE
CONTENTS. — 1. General characteristics and composition of human urine.
2. Formation of urea. 3. Formation of uric acid and the purine bodies. 4. Forma-
tion of creatine and creatinine. 5. Formation of hippuric acid and aromatic
substances (ethereal sulphates). 6. Formation of pigments and chromogens
(urochrome, urobilin, uroerythrin, indican). 7. Formafion of non- nitrogenous
organic acids (oxalic acids, lactic acids, volatile fatty acids). 8. Carbohydrates of
normal and pathological urine (glucose, lactose, animal gum, acetone, glycuronic
acid). 9. Proteins of normal and pathological urine (serum -albumin, serum-
globulin, fibrinogen, enzymes). 10. Inorganic constituents of urine (chlorides,
sulphates, alkaline and earthy phosphates, carbonates, ammonium compounds).
11. Toxicity of urine and uraemia.1 Bibliography.
WE stated in the introduction to the last chapter that the kidneys
represent the principal organ of excretion in the animal body.
All the waste products, in fact, which originate in the foods that
are introduced into, and absorbed from the digestive canal leave
the body sooner or later by the kidneys, with the exception of the
few substances permanently retained, of those which are con-
stituents of the body at the moment of death, and of those, lastly,
which are eliminated in the form of gas or fluid by the other
excretory systems — the lungs, surface of the skin, and internal
mucous surfaces, particularly the mucous membrane of the
intestines. If we sum up the products not eliminated by the
kidneys, they obviously form a very minor quantity in comparison
with the sum of the metabolites that are thus excreted. The
predominating importance of the renal apparatus is plain, when
we consider the chemical nature of the excreta eliminated by the
kidneys. The majority of the nitrogenous compounds, i.e. the
waste products of the proteins, which form the main substrate of
living protoplasm, are discharged with the urine.
I. So much can be gathered from the composition and
character of the Urine as to the general metabolism of the body
and its principal organs and tissues, that it is no wonder this
1 EDITORIAL NOTE. — Owing to the impossibility of giving adequate directions
for laboratory work in connection with this chapter, the technical instructions
contained in certain passages of the Italian text have been entirely omitted from
the English version.
377
378 PHYSIOLOGY CHAP.
subject should have been investigated long before chemistry had
developed into an exact science. The earliest attempts of Van
Helmont to determine the nature and origin of the urinary con-
stituents date from the commencement of the seventeenth century.
Towards the middle of the same century, Brand, the alchemist-
physician of Hamburg, first obtained phosphorus from the urine,
while Kunkel, shortly after, described it more exactly. At the
beginning of the eighteenth century the famous Boerhaave made
the first analysis of urine, which is now only of historical ioterest,
but was thought marvellous at the time it was drawn up.
The most important nitrogenous constituent of urine, which
received the name of urea, was first recognised by Hilaire Eouelle
(1775), the younger brother of that G. Eouelle who was Lavoisier's
teacher. But the actual discovery of urea was due to Cruikshank
(1797), who first obtained crystals of urea nitrate. Scheele and
Bergmann (1775-88) discovered the compound now termed uric
acid, in calculi of the bladder. Fourcroy and Vauquelin (1799)
made a more profound study of the chemistry of urine, and
particularly of the composition of the urinary calculi. The first
quantitative analysis of urine, by Berzelius (1809), is quoted in
the classical Text-book of Johannes Miiller. Comparison of this
with the analyses of modern times shows the enormous advances
made in the chemistry of the urine, owing to the labours of a long
succession of workers, between the beginning and the close of the
nineteenth century.
We must limit ourselves to a summary of the characters and
composition of urine, referring for more minute details to recent
text-books of chemical physiology, and the special monographs
which deal with this subject from the standpoint of theoretical
and practical medicine.
Human urine, when first given off from the bladder, is normally
a clear straw-coloured fluid, with a peculiar, somewhat aromatic
odour, saltish-bitter taste, acid reaction, and mean specific gravity
of 1020.
The amount of urine excreted in the 24 hours varies greatly
under different conditions : the age and weight of the individual,
the diet, the quantity of fluid imbibed, the season or external
temperature, muscular rest or exercise, etc. In a normal, well-
nourished adult it may fluctuate, owing to these or other circum-
stances, from 1300 to 1600 grms. in man, from 900 to 1200 grins.
in woman.
The specific gravity of the urine varies with the amount
secreted, and the content of solid substances dissolved in it.
Under normal conditions the specific gravity, as measured bj
the urinometer, varies between 1016 and 1025. To calculate with
approximate accuracy from these values the amount of solids dis-
solved in 1000 c.c. urine, it is only necessary to multiply the two
vii KATABOLIC CONSTITUENTS OF UKINE 379
last figures of the specific gravity by the constant coefficient '2'33
(Haeser). A litre of urine of normal mean specific gravity, e.g.,
contains solids to an approximate amount of 20 x 2'33 = 46'60
grms. ; and 1J litre of this urine secreted on an average in the
24 hours contains 20 x 23 x 31'5 = 69'90 grms. solid substances.
The acidity of the total urine in man in the 24 hours is, under
normal conditions, about equivalent to that of 2 grms. oxalic acid,
with which it is usually compared. It is largely due to the
presence of acid sodium phosphate (Liebig). But the degree of
acidity naturally varies at different times of the day. During
gastric secretion, owing to the formation of hydrochloric acid and
reabsorption of the liberated sodium in the blood, the alkalinity
of the blood increases and the acidity of the urine therefore
diminishes (01. Bernard, Bence-Jones, Gley), increasing again
when gastric digestion is over. The nature of the diet has more
influence on the reaction of the urine. With vegetable food,
which contains an excess of alkali, the acidity of the urine
diminishes, so that it may exhibit a neutral or amphoteric, some-
times even an alkaline reaction, when, e.g., only potatoes, which are
very rich in potassium salts, are eaten. On a flesh diet, on the
contrary, in which the earthy bases predominate, the urine is
•always distinctly acid.
For the same reasons the urine of herbivora is normally
alkaline and that of carnivora acid. But in fasting, when both
carnivora and herbivora consume their own tissues, the urine of
the latter also becomes acid (01. Bernard).
The acidity of human urine sometimes increases for a certain
time after micturition, owing to a fermentation which gives rise
to the development of new acid substances (Scherer). This causes
a precipitation of acid urates which makes the whole of the urine
cloudy, and slowly forms a sediment consisting principally of
urates, plus oxalates, mucus and desquamated epithelial cells from
the urinary passages. When present in large amount, these
urates may be precipitated, as the urine cools, independent of
any fermentation. In this case the acidity of the urine is not
increased, but is diminished, owing to the precipitation of the acid
urates (Voit and Fr. Hofmann).
As was said above in discussing the reaction of the blood (see
Vol. I. p. 94), recent work in chemical physiology has greatly
modified our notions as to the reaction of urine and of all the
tissue fluids in general. Thus, according to the results of
Auerbach and Friedenthal (1903) either with physico-chemical
methods, or by simply using a suitable indicator (e.g. phenol-
phthalein), human urine always has a neutral or weakly acid
reaction, even when an alkaline reaction is indicated by litmus.
In fact, neither litmus paper nor methyl orange can be used as
indicators in presence of carbonic acid.
380 PHYSIOLOGY CHAP.
According to Hober (1903) the physico-chemical concept must
be distinguished from the purely chemical concept of acidity.
While physico-chemical methods only measure the concentration
of the hydrogen ions actually present, i.e. dissociated from the
molecules of the acid, the titrimetric (chemical) method measures
not only these, but also the hydrogen ions whicli at the outset of
the experiment are still bound up in the acid molecules, and only
become dissociated later on ; that is, it measures both the actual
and the potential hydrogen ions (Ostwald). In the case of urine
also we must distinguish between these two acidities, the ion-
acidity and the titration-acidity, which are, not only theoretically,
but also (as appears from certain experiments of Hober) practically,
two distinct magnitudes, varying independently of each other, and
each having its special significance, which must not be neglected
in judging of the secretory state of the kidneys, or of general
metabolism.
After a longer or shorter time (two or three days) the urine
undergoes ammoniacal fermentation, and the reaction becomes
alkaline. This is due to the action of organised ferments (usually
Micrococcus ureae and Bacterium ureae} which are able to convert
urea into ammonium carbonate. This fermentation constantly
occurs in urine exposed to non-sterilised air, but it may also take
place in the urine within the bladder, if non-sterilised surgical
instruments are introduced The urine undergoing alkaline
ammoniacal fermentation gives off a foetid ammoniacal odour and
becomes turbid, owing to the formation of a sediment which
consists principally of crystals of ammonium-magnesium phosphate
and ammonium urate. According to Musculus the urea micro-
organisms secrete a diastatic enzyme which is the direct agent of the
cleavage, and which can be isolated by precipitation with alcohol.
The molecular concentration of human urine, as determined
by the cryoscopic method, i.e. by the lowering of the freezing-point,
differs considerably from that of blood serum. While in the
latter A = 0'55° C., in the urine it may reach the value of A = 1*85° C.
(Winter), or even of A = 2-3° C. (Dreser). This higher molecular
concentration of urine as compared with blood plasma is not,
however, constant ; even in man it occasionally falls below that of
the blood, and may reach a minimum of A = 0'4° C. (Dreser). We
shall discuss the value of these data for the theory of the mechanism
of urinary secretion at a later point.
H. Frenkel and J. Cluzet (1901) also drew attention to another
physico-chemical property of urine: its surface tension. Since
the surface tension of a solution depends not only (as in molecular
concentration) on the number but also on the chemical nature of
the dissolved molecules, it is clear that, under given conditions,
the changes in surface tension may afford indications as to the
chemical constitution of a solution. The surface tension of urine,
VII
KATABOLIC CONSTITUENTS OF UEINE
381
e.f). (which under both normal and pathological conditions is
always less than that of distilled water), is increased by mineral
salts, and diminished by organic substances, such as bile salts.
The addition of bile to urine causes a perceptible alteration in its
surface tension, even with a concentration so low that chemical
tests are not perceptible (supra, p. 145).
The determination of surface tension in any given fluid is most simply
ascertained by counting the number of drops required for 1 c.c. of the fluid to
fall drop by drop from a pipette. The number of drops is inversely pro-
portional to the magnitude of surface tension.
The chemical composition of urine, both in man and animals, is
very complete, as shown by the number of individual substances
that can be chemically isolated, and recognised in it. The majority
of these, however, are present in such minute quantities under
normal conditions that a large amount of urine is required before
even a trace of them can be detected.
Only a limited number of organic and mineral substances are
found dissolved in the urine in any appreciable quantity. Among
the former urea enormously predominates; next follow uric acid
and creatinine, but in much smaller amount : among the latter,
sodium chloride predominates, and the sulphates and the alkaline
and earthy phosphates are the other principal constituents.
The following table will assist us in realising the quantitative
relations between the principal constituents of the urine, and the
maximal extent to which they vary with the diet. It gives the
analyses obtained by Bunge (1887) from a healthy youth, whose
total urine secreted in the 24 hours was collected, on an exclusively
flesh, and on an exclusively vegetable diet ; the former consisted of
veal seasoned with common salt, the latter of wheat bread with a
little butter and salt. To these data are added the averages
obtained by Parkes, under normal conditions, with an ordinary
mixed diet.
Urinary Constituents.
Meat (Bunge).
Bread (Bunge).
Mixed Diet (Parkes).
"olume of urine .
1672 c.c.
1920 c.c.
1500 c.c.
c\ • ("Urea
Organic KT • A -j
i , " i Uric Acid
substances ,-, , • •
[Creatinine
67,200 gi
1,398
2,163
q 1
(70,761
J grs.
20,600 g
0,253
0,961
*' 121,814
j" grs.
33-18 g
0-55
0-91
'S.
J
34-64
" grs.
^Potassium
3-308
<
1-314
}
2-50
•\
Sodium .
3-991
3-923
11-09
Mineral
substances"
Calcium .
Magnesium
Chlorine .
0-328
0-294
3-817
19-849
grs.
0-339
0-139
4-996
1 13-635
j grs-
0-26
0-21
7-50
26-73
' grs.
Sulphuric acid
Phosphoric acid
4-674
3-437
•
1-265
1-659
1
2-01
3-16
'
382 PHYSIOLOGY CHAP.
The urine gives an acid reaction with the flesh diet and mixed
diet, as well as on a diet of bread. It is easily seen from the
above data that in all three tables the content of chlorine and
sulphuric acid is more than sufficient to combine with the whole
of the alkali in the form of chlorides and sulphates.
It is convenient in considering the total organic and inorganic
substances found in the urine to classify them into different
groups based on the approximate criteria of their characteristic
affinities, chemical constitution, and origin. Hoppe-Seyler and
Halliburton distinguish the following groups of substances in the
urine : —
(a) Nitrogenous Substances of the Fatty Series. — Among these
are urea, uric acid, allantoin, xanthine, guanine, creatine, creatinine,
sulphocyanic acid.
(5) Non-nitrogenous Substances of the Fatty Series. — These
include the fatty acids of the series CwH2nO2, oxalic acid, lactic
acid, glycerophosphoric acid, small quantities of carbohydrates.
(c) Compounds of the Aromatic Series. — These include the
ethereal sulphates formed from phenol, cresol, pyrocatechol, indoxyl,
hippuric acid, the aromatic oxy-acids.
(d) Organic Substances not exactly determined. — This group
includes the pigments and chromogens of urine, the enzymes
(especially pepsin), the mucin and a small amount of proteins.
(e) Inorganic Salts. — These are sodium and potassium chloride,
potassium sulphate, sodium, calcium and magnesium sulphate,
silicic acid, ammonium compounds and calcium carbonate.
(/) Gases, i.e. nitrogen and carbonic acid.
To these substances normally present in human urine, man]
others are added in abnormal conditions and special diseases, i.t
serum-albumin and other proteins, haemoglobin, and methaemc
globin, bile pigments and salts, leucine and tyrosine, glucc
and lactose, glycuronic acid, fat, lecithin, cholesterol and cystine.
To these we must add a number of other substances derived
from special foods and drugs. Lastly, there are organised
cells, e.g. epithelia of kidneys and bladder, urinary casts, blood
corpuscles.
We must briefly run through the characteristics and origin of
the principal substances comprised in these groups.
II. Among the nitrogenous urinary constituents of the fatty
series, Urea is the most important, and is the end-product of protein
katabolism. Chemically considered it is a carbamide, i.e. carbonic
acid, in which the two hydroxyl groups are substituted by two
(amino) groups (NH2), and its formula is CO(NH2)2. It was
first obtained artificially by Wohler in 1828 by heating ammonium
cyanate, which is the isomer of urea (NHJ'O'CN.
By heating with water at 140° C., by boiling with acids or
alkalies, or by the action of the enzymes secreted by the bacilli of
vii KATABOLIC CONSTITUENTS OF UEINE 383
amrnoniacal fermentation, urea is readily converted into ammonium
carbonate : —
CO
As we see from the preceding table, about 30 grms. urea are
eliminated with the urine in the 24 hours, on a normal mixed diet.
Yvon and Berlioz (1888) obtained from a large number of
comparative researches on the daily output of urea, 26'5 grms. for
man and 2O5 grms. for woman. As shown by Buuge's results, the
urea increases considerably with an exclusively flesh diet and
diminishes in a vegetable diet ; this is in evident relation with
the amount of nitrogenous substances introduced. It also bears a
relation to the body- weight and age of the individual. According
to Uhle's analyses, the quantity of urea in the 24 hours varies with
the age with each kilogramme of body-weight in the following
proportions : —
From 3 to 6 years . . .1 grm.
„ 8 to 11 „ . . . 0*8 grms,
„ 13 to 16 „ . . . 0-4-0-6 grms.
In Adults ..... 0-37-0-6 grms.
The secretion of urea increases directly after a meal (par-
ticularly if rich in protein) and reaches its maximum in 4 hours
(Tschlenoff), or in 7-10 hours, when the total quantity of the
urine secreted becomes maximal and its concentration minimal
(Carnerer, 1888).
As we saw in Chapter V. (p. 335 et seq.), urea is formed not in
the kidneys but in the liver. This fact was first discovered by
Meissner, and subsequently confirmed by Brouardel, Koster, v.
Schroder, Minkowski, and others. It is, however, probable that
other organs (spleen, lymphatic glands, glands in general) take
some share in the formation of urea. Although it diminishes
greatly it does not entirely cease after removal of the liver or
in profound morbid changes of this organ.
The problem of the origin of urea, i.e. the process of its
formation in the body, is one of the most important, and at the
same time one of the most difficult in physiology. It is certain
that urea, like all the other nitrogenous constituents of urine,
originates in the decomposition of the complex protein molecule ;
but there is great discussion as to whether, or how far, it is
directly derived from the successive oxidation of these molecules,
or whether it is formed by synthetic processes indirectly, i.e. after
the protein molecule has undergone the maximal degree of
cleavage.
Urea was formerly supposed to be the end-product in the
oxidation of the protein molecule, while uric acid, creatinine,
xanthine, and in general the whole group of the nitrogenous
substances of the fatty series which are present in urine, repre-
384 PHYSIOLOGY CHAP.
sented different stages in this oxidation, and as such were the
precursors of urea. This theory was inspired by the undeniable
fact that the oxidising process is the most important in the
animal body, as also by the fact that in many reactions uric acid
and creatinine give rise to urea by oxidation.
Later work, however, has shown that urea cannot be looked
on merely as an oxidation product of protein, although it un-
doubtedly comes indirectly from the cleavage of the protein
molecule.
We saw in Chapter IV. (p. 211) that protein, when acted
upon by the tryptic enzyme, gives rise by simple hydrolytic
cleavage to large quantities of peptone, leucine, and tyrosine
(Kiihne). Other researches have shown that the same process
gives rise to aspartic acid (Salkowski, Knieriem) as well as to large
quantities of glycocoll, on the tryptic digestion of gelatin and
collagens in general (Nencki). These same cleavage products
(which are known as ammo-acids) are obtained from proteins by
long boiling with strong acids or alkalies. According to the most
recent work, a series of basic compounds is also formed by the
same means, i.e. lysine, arginine and histidine (Hedin).
All these nitrogenous compounds into which the complex
protein molecule breaks up may perhaps be regarded as precursors
of urea, the more so since some of them, particularly leucine and
tyrosine, if not normally present in the urine; are found in certain
tissues, e.g. spleen and pancreas.
Experimental evidence shows that some of these substances are
converted into urea in the body. On injecting leucine or glycocoll
into dogs, they are not found in the urine, but, on the other hand,
the urea increases (Schultzen and Nencki, Salkowski). Aspartic
acid, again, if given to the animal, reappears in the urine only in
the form of urea (Kuieriem).
But the transformation of this and other amino-acids into urea
can only be chemically explained by synthetic processes. Leucine,
glycocoll, and aspartic acid contain only one atom of nitrogen,
while urea contains two. It is, therefore, probable that amino-acids
previous to their conversion into urea undergo a further decom-
position in the body, leading to the formation of ammonia (NH3).
The ammonia combines with the carbonic acid, forming
ammonium carbonate, which is again converted, with the loss of
one molecule of water, into ammonium carbamate, as shown by the
equation : —
/ONH,
C0< -H20 = CO
\ONH4
The ammonium carbamate is then converted with loss of a seconc
molecule of water into urea : —
vii KATABOLIC CONSTITUENTS OF UEINE 385
C0<^ 4-H20 = CO<'
\NH2 \NH2
Schmiedeberg is the author of the theory that urea is derived
from ammonium carbonate. He demonstrated that on treating
protein with barium hydrate ammonium carbonate is formed, which
when injected into the body is (at least partly) converted into urea
with loss of two molecules of water. The theory that urea may
be formed from the dehydration of ammonium carbamate is due to
Drechsel (1875), who showed that ammonium carbamate is formed
on oxidising leucine and glycocoll. When an aqueous solution of
these substances is exposed to the electrolytic action of 4-6 Grove
cells (with an automatic commutator, by which the direction of the
current can be rapidly changed, so as to produce at each electrode
alternate processes of reduction and oxidation), it is converted
through an intermediate product into urea : —
C0< +O = CO< +H20
\NH2 \NH2
Ammonium carbamate. Intermediate product.
/ONHo ^NH2
'
C0<
\NH2
Urea.
This theory of the derivation of urea either from ammonium
carbonate or from ammonium carbamate, by successive and
alternate oxidations and reductions taking place in the liver, has
been substantially confirpaed by the experiments of v. Schroder,
Salomon and Minkowski, as also by those of Nencki, Hahn,
Pawlow and Massen, on dogs with an Eck's fistula, to which we
referred in Chapter V. (p. 335). Taken as a whole, the results of
these experiments show the hypotheses of Schmiedeberg and
Drechsel to be justified, and further make it probable that carbamic
acid and ammonium carbonate are katabolic products from the
spleen, pancreas, and gland cells of the intestinal tract, which,
when absorbed and carried by the portal system to the liver, are
converted into urea.
On another theory, maintained by Hoppe- Seyler, urea is
derived from cyanic acid. This is founded on the fact that part of
the amino-acids (leucine, tyrosine, glycocoll) introduced into the
body, appear in the urine in combination with the group (CO'NH)
or cyanic acid, forming the so-called uramino-acids (Salkowski,
Hoppe-Seyler, Baumann). This fact leads the above authors to
conjecture that cyanic acid can be formed in the body. On this
VOL. II 2 C
386 PHYSIOLOGY CHAP.
supposition urea can be derived from cyanic acid as follows
(Salkowski) :—
2(HOCN) + H2O = CO<' +C02
Cyanic acid. Urea.
It may also be assumed (Hoppe-Seyler) that the cyanic acid
on combining with ammonia forms ammonium cyanate (NH4OdNT),
which is isomeric with urea (CO'(N'H2)2) and from which, as we
saw, Wohler obtained urea by synthesis.
To this theory Hofmeister objected that cyanic acid had not
yet been discovered in the body, and particularly in the liver. It
was also noted that if salts of ammonium, or ammonia, were
introduced into an organism poisoned with cyanic acid, the
syndrome was not altered, showing that the two substances did
not combine to form urea, as assumed by Hoppe-Seyler.
Hofmeister experimentally discovered an important fact, viz. :
that urea can be obtained from a large series of organic com-
pounds, by oxidation with permanganate of potash, in the presence
of ammonia. Among such are ovalbumin, glutin, asparagine,
leucine, glycocoll, hydrocyanic acid, and lactic, malic and tartaric
acids. This shows the extreme importance of the oxidising
processes to the formation of urea outside the body. But it has
not at present been decided how far similar processes may occur
within the living body.
III. In the urine of birds and reptiles nearly all the nitrogen
introduced is eliminated in the form, not of urea, but of uric acid.
Uric acid is often absent from the urine of carnivora, while that of
herbivora shows no trace of it. In human urine, however, it is
always present in a small quantity which normally fluctuates
between 0'25 grm. and 140 grm. On an exclusively vegetable
diet it rarely exceeds 0'3 grm. in the 24 hours : on an exclusively
flesh diet it may reach 2 grms. or more. Its relation with the
total nitrogen of the urine is from 1 to 3 per cent ; its relation with
the urea may vary from 1*15 to 1*82.
Uric acid is not normally present in human blood, but it
has been noted in minute quantities in the glandular organs,
particularly in the liver, spleen, and lungs (Gorup-Besanez and
others). Evidently, therefore, it is not a product of the kidneys,
the more so as in pathological conditions (arthritis, leucaemia,
pneumonitis, pulmonary tuberculosis) it also occurs in the blood.
It is normally present in the blood of birds (Salomon, Meissner),
and becomes abundant there after ligation of the ureters
(Colasanti).
The empirical formula of uric acid is C5H4N403. One atom
of hydrogen is easily replaced by bases. On bringing uric acid
vii KATABOLIC CONSTITUENTS OF URINE 387
into a solution of sodium carbonate, acid sodium urate is obtained
(C5H2NaN403). On dissolving it in caustic alkali, the second atom
of hydrogen is replaced, and the neutral urate (C5H2Na2N403),
which is highly unstable, is formed.
Both uric acid and the acid urates are soluble with difficulty
in water : 6-7 litres of water are required to dissolve 1 grin, uric
acid at body temperature (Bunge). This would lead us to suppose
that the urates are present in urine in the form of neutral salt.
But against this conjecture must be set the fact that the urine,
which is clear and acid when passed, forms on cooling to the
temperature of the air, especially in winter, the sedimentum
lacteritium, which contains large crystals of uric acid coloured dull
yellow by the red pigment of the urine. The crystalline sediment
dissolves in heating the urine to body temperature. C. Voit and
Hofmann demonstrated that this fact depends on the presence in
the urine of acid sodium phosphate, which when the urine cools
is converted into neutral phosphate,' thus removing the bases from
the urates, and causing the precipitation and crystallisation of
free uric acid. On the formation of the sediment the acidity of
the urine falls and rises again when the sediment re-dissolves,
the uric acid being once more converted into acid urate.
As regards the origin of uric acid, it was formerly held that
it arose from incomplete oxidation of the cleavage products of the
proteins (Liebig). The following facts can be mustered in support
of this view : (a) by means of oxidising agents uric acid can
readily be converted into urea and carbonic acid outside the
body; (6) when introduced into the body of a dog it almost
entirely reappears in the urine in the form of urea (Zabelin,
Frerichs, Wohler) ; (c) when mixed with the blood and circulated
in the liver, it is converted into urea (Ascoli).
These facts, however, do not prove that urea is normally
formed by direct oxidation of uric acid as shown in the last
paragraph. On artificially obstructing respiration in dogs, cats,
and rabbits (Senator), or on bleeding these animals (Naunyn,
Riess), no perceptible increase of uric acid is obtained.
It is a striking fact that the ingestion of ammonium salts
increases the production of uric acid in birds (v. Schroder), and
that urea injected into the portal vein is partly converted into
uric acid (Meyer and Jaffe). After excising the liver in geese,
a diminution of uric acid and corresponding increase of ammonia
and lactic acid has been observed in the urine, which seems to
show that in birds the liver is able to form uric acid synthetically
from ammonia and lactic acid (Minkowski). On the other hand,
it has been shown that ammo-acids (leucine, glycocoll, aspartic
acid), which give rise to a formation of urea in mammals, also
give rise to uric acid in birds (Knieriem).
As regards mammals and man, however, no data can be
388 PHYSIOLOGY CHAP.
adduced to show that uric acid is derived from ammonium com-
pounds. On the contrary, an important series of experimental
data show that uric acid in mammals and man is derived directly
from the group of the purines (traces of some of which exist in
the urine), which in their turn are formed from the nuclei n.^ :
these nucleins in the cell nucleus of plants and animals correspond
with what histologists term chromatin.
The work of Kossel and his school (1879-96), to which we
owe the greater number of determinations of the mother-substane^
of the purines, has proved the existence in the organs, tissues, and
cells of a group of bodies termed nucleins, which are present in the
free state in the form of nucleic acids, or in combination with
protein in the form of nucleo -protein. Such organs are the
thymus, spleen, lymph glands, spermatozoa (particularly of
salmon and sturgeon), erythrocytes (of geese), etc. They further
demonstrated that the purines, e.g. xanthine, hypoxanthine,
guanine, adenine, sarkine, etc.", can be readily obtained from these
tissues or cells. Hence nuclein is probably the source of the
xanthine bodies.
On the other hand, Fischer (1884) has clearly demonstrated
that there is a close relation in the constitution of purines and of
uric acid, that they contain a nucleus which he terms purine, and
that uric acid, xanthine, and hypoxanthine might be regarded as
oxidation products of this nucleus.
The most important experimental data on the physiological
side which confirm this theory and tend to clear up the ques-
tion of the origin of uric acid in the body, are specially due
to Horbaczewskj (1889-93). Minkowski (1887) had already
obtained increase of uric acid in fowls after the injection of
xanthine bodies, and Mares (1888) recognised that uric acid
formed by a process distinct from that which gives rise to ui
because the relative quantity of urea changes at different horn
during abstinence and after an abundant meal.
Starting from the well-known clinical fact that increase of
uric acid is constant in Leucaemia splenica, Horbaczewski sought
to discover if it were possible to obtain xanthine, hypoxanthine,
and uric acid from splenic pulp. The positive results obtaine
show that the splenic pulp, which contains many leucocytes,
contains the mother substances of the purines and uric acid,
oxidising the splenic pulp with defibrinated blood, hydroge
peroxide, or air, uric acid is obtained : when, on the contra
it is hydrolysed by boiling, xanthine and hypoxanthine result.
These experiments of Horbaczewski were confirmed in Ital]
by Giacosa, who obtained uric acid not only from the spleen but
also from the liver when left to oxidise with blood ; by Zagari anc"
Pace, who obtained it from the thymus by the same method ; anc
by Ludowenj and Formanek in Horbaczewski's laboratory, whc
vii KATABOLIC CONSTITUENTS OF UEINE 389
obtained uric acid from a variety of other tissues and organs :
brain, kidneys, liver, gastro-intestinal mucous membrane, lungs,
thynuis, muscles, etc.
That uric acid arises from nuclein, not merely in vitro as
Fischer showed but also in vivo, was demonstrated by Horbaczewski
on man by administration of nuclein, which produced an increase
of uric acid in the urine. He also showed that the increase of
uric acid coincided with an increase of leucocytes in the blood,
which suggests that the circulating nuclein caused a hyperforma-
tion of leucocytes on the part of the lymph organs. On these
facts he based the theory that nuclein is derived from the
leucocytes, that uric acid is formed from the nuclein, and that all
the means which increase the leucocytes determine a simultaneous
increase in the formation and elimination of uric acid.
Clinical and experimental investigation of this theory, however,
militate against the supposed parallelism between the increase in
the number of leucocytes of the blood and the uric acid content of
the urine, although they confirm the fact that there is a relation
between the nuclein introduced and the uric acid excreted.
Kriiger and Wulff (1894) invented a method for estimating
the total nitrogen of the purines, and endeavoured by its means
to establish the "ratio between the nitrogen of the uric acid and
that of the purines. They saw that this ratio varies considerably
in normal individuals, but that the nitrogen of the uric acid
always exceeds that of the purines, on an average by 4 : 1.
Weintraud (1895) studied the effect of feeding substances rich
in nuclein on the elimination of uric acid, by substituting thymus
— which is an organ very rich in nuclein — for alimentary protein,
in an adult man. He found a relative increase in the elimina-
tion of uric acid without any constant augmentation in the
number of leucocytes in the blood. From this he concluded that
the purine bases are formed in the alimentary canal, independent
of leucocy tosis, and that on absorption they determine an incre-
ment of uric acid.
Zagari, in collaboration with Pace (1897), experimented on
six normal and two leucaeinic subjects and one nephritic, and
observed that when thymus and nuclein were added to the usual
diet of these individuals, there was no constant hyper-production
of leucocytes, but there hardly ever failed to be a considerable
increase of uric acid, both in healthy subjects and in invalids :
that in leucocytosis of varying degree the value of the uric acid
excretion was not parallel with the fluctuations of the leucocytosis ;
that in the rare cases in which there was no increase of uric acid the
total nitrogen of the urea did increase. We are not at present
able to account for these differences of result, which are certainly
due to special conditions of metabolism in different individuals.
Laquer (1896) studied the influence of water and milk on the
390 PHYSIOLOGY CHAP.
elimination of the purines. On administering water he saw that
the nitrogen of the uric acid and that of the purine bases was
almost doubled ; on administering milk the nitrogen of the purine
bases was more than doubled, while the uric acid, on the contrary,
diminished — the normal ratio between the two being inverted.
These results were confirmed by Zagari and Pace.
These and other experiments, which space compels us to omit,
are sufficient to show that the production of uric acid is largely
influenced by the nature of the diet ; it increases on ingestion of
substances rich in nuclein and purines, and diminishes on ingestion
of foods in which, as in milk, they are scanty. As urea represents
the final result of the conversion of alimentary protein, so uric acid
and the purines represent the katabolic products of the alimentary
nucleins.
Of the later work on this subject special mention must be made
of that of E. Burian and H. Schur (1900-1). They endeavoured,
by a number of researches, to ascertain the fate of the purine
bodies in human metabolism, and arrived at the following results : —
Every healthy adult eliminates a definite and constant quantity
of purine bodies by the urine. These result from metabolic pro-
cesses, which are to a certain extent independent of the diet. The
amount of this endogenous purine, which, as we have said, is
approximately specific and constant for each individual, can be
directly determined on dieting the subject for a sufficiently long
period exclusively on foods that contain no nucleo-protein (milk,
cheese, eggs, potatoes, rice, salad, white bread, etc.). In ordinary
human diet these endogenous purines are reinforced in a variable
degree by other purines which are derived from the preformed
purines of the food, and must therefore be distinguished by the
name of exogenous or alimentary purines. The usual fluctuations
in the elimination of the purines depend mainly upon their varying
content in the food. The amount of exogenous puriue eliminated
with the urine does not, however, correspond exactly with the
amount of alimentary purine ; a greater or lesser part of the latter
is broken up in the body by decomposition of the purine-ring.
The amount of nitrogen eliminated in the form of endogenous
purine in the course of the day fluctuates between O'l and 0'2
grins. The principal formation of endogenous purine takes place,
according to Burian's latest work, in the muscles.
In all mammals, both the exogenous and the endogenous
acid are an intermediate product of metabolism, i.e. one whici
undergoes or may undergo further cleavage in the body. Thai
this holds also for endogenous uric acid is shown by the fact that
in dogs, after removal of the kidneys and the liver, which is
the most important organ in the destruction of uric acid, endo-
genous uric acid is found in the blood, which is not the case after
removing the kidneys only. Since, however, the mammalian body
vii KATABOLIC CONSTITUENTS OF UEINE 391
has the power of breaking up both endogenous and exogenous uric
acid, and since the faculty of destroying uric acid manifested by
different organs is very considerable, a fraction of the uric acid
which circulates in the blood is always eliminated as such, i.e. that
which passes with the blood directly to the kidneys, and thus
escapes further decomposition.
The mean value of the fraction of uric acid excreted is approxi-
mately constant for each individual ; so that in every case there is
an integral factor by which the quantity of uric acid eliminated
must be multiplied, in order to calculate approximately the total
quantity of uric acid that enters the vascular circulation.
This constant integral factor is the same in man even for
different individuals, while in carnivora there may be individual
differences. It varies, on the contrary, very much in the different
species of mammalia ; carnivora eliminate only about -^ or -^ of
the uric acid which reaches the circulation in an unaltered form ;
rabbits excrete a larger amount, about ^ ; man, as a rule, fully \.
These striking differences evidently depend on the varying number
and capacity of the organs which destroy uric acid in the different
species of animals.
IV. Creatinine, as we have seen, is one of the principal nitro-
genous constituents of urine. The amount excreted in man in 24
hours varies considerably — according to Neubauer from 0'6 to T3
grms. ; according to Johnson from 1-I7 to 2gl grms. ; according to Hof-
mann from 0'5 to 0-9 grms. In young and robust individuals Grocco
as a rule obtained 0'98 grm. on an average, while in old people of
70 only 0'45 grm. was obtained. But the amount varies greatly
with the diet. We saw in fact that in the healthy young man on
whom Bunge experimented 2*16 grms. creatinine were obtained
with an exclusively flesh diet, and only 0'91 grm. on a regimen
consisting entirely of bread.
The creatinine of the urine is certainly derived from the
creatine of the muscles, from which it differs only by the
absence of one molecule of water. According to Voit and Meissner,
a small quantity of creatine is always present in the urine of
mammals along with the creatinine ; this increases when the urine
secreted has an alkaline reaction. It is further to be noted that
the reciprocal transformation of these two substances by hydration
or dehydration is very easy. In an acid solution the creatine is
dehydratised and converted into creatinine ; in an alkaline solution
the opposite occurs by hydration.
Crealine is the most abundant nitrogenous katabolic product
of the proteins in the body. In the muscles alone creatine is
present in a quantity of about 3 per cent, and the muscles of
adult man as a whole contain about 90 grms. of this substance.
Seeing that urea, of which 30-40 grms. are daily excreted with
the urine, is present only in small quantities in the blood, and
392 PHYSIOLOGY CHAP.
has not been detected at all in muscle, it might reasonably be
assumed that most of the creatine of the muscles is converted
into urea, and "given off into the blood in proportion as it is formed,
to be eliminated from the blood with the urine by the kidneys.
But the fact, as demonstrated by Meissner (1865, 1866, 1868), that
the whole of the creatine ingested, or injected into the veins,
passes into the urine without conversion into urea, contradicts this
opinion, as maintained by some physiologists. Bunge, however,
holds that although the creatine introduced into the body is
not converted into urea, this does not prove that such a conversion
does not occur in the creatine formed by muscle, since muscle
only picks up the nutrient substances from the blood, and not the
katabolites artificially introduced into the circulation, such as
it habitually excretes into the blood. He thinks it highly
probable that creatine is a mother substance of urea, more
particularly as creatine contains three atoms of nitrogen and
only four atoms of carbon.
These hypotheses of Bunge do not appear to us to be com-
patible with Baldi's investigations (1889), carried out in our
laboratory upon Succi during his fasts. Baldi found that the
creatinine never entirely disappeared from the urine between the
1st and 30th days of fasting, but that it diminished in proportion
with the total nitrogen of the urine. If the urea is derived from
the creatine, then during inanition, when the organism is living
at the expense of its own tissues, the creatine should be entirely
converted into urea and disappear from the urine. If it does not
disappear even when the nitrogen of the urine is reduced to a
minimum of 3 grms. per diem, but keeps in almost constant ratio
with the urea, this implies that the latter is formed (at least
mainly) by processes which are entirely independent of the con-
version of creatine.
Although creatine has been synthetically obtained by Volhz
and by Strecker from the combination of sarcosine with cyanamide,
it has not yet been artificially produced by cleavage of the different
proteins. By the hydrolytic cleavage, with acids, of caseinogen,
conglutin, gelatin, and other proteins the compound arginine hs
been obtained, which is homologous with creatine and creatinine
(C4H7N3O). Both from creatine and arginine urea is split off on
boiling with baryta water. This shows that the whole of the urea
may not be formed synthetically after oxidation, but that part
of it may be formed by hydrolytic cleavage from either creatine or
arginine.
A large part of the creatinine of the urine of man and carnivora
comes directly from the creatine of the alimentary flesh. Another
part is formed from the katabolic processes in the muscles of the
body, which, as stated above, contain a considerable amount of
creatine. The urine of herbivora also contains creatinine, like the
vii KATABOLIC CONSTITUENTS OF UKINE 393
urine of fasting, and that of dogs fed on meat that has been
exhausted, and entirely or almost entirely deprived of its creatine
(E-ubner). Another fact which shows that creatinine is specially
formed by the muscles, is that muscular work and fatigue increase
the quantity of creatinine in the urine (Grocco, Moitessier,
Ackermann).
V. The urine of man and other mammals constantly contains a
group of aromatic compounds, among which hippuric acid largely
predominates. This results from the combination of benzoic acid
with glycocoll with loss of one molecule of water : —
CBH6COOH + CH2(NH2).COOH = C6H5CO - NH.CH2.COOH + H20
Benzoic acid. Glycocoll. Hippuric acid.
Hippuric acid (in combination with alkalies), although it is
present only in small quantities in human urine, is never absent
even during an exclusively flesh diet and in fasting. It arises
from the aromatic substarices of the food, which are converted as
the result of bacterial fermentation in the intestinal canal into
benzoic acid : this, after absorption, combines with the glycocoll,
with formation of hippuric acid, by loss of water. These aromatic
substances come from hydrolytic cleavage of the proteins, which,
as we know, contain an aromatic nucleus. Glycocoll is another
cleavage product of the same substances, formed by katabolic
processes in the tissues.
With an ordinary mixed diet the hippuric acid content of the
urine fluctuates from O'l to I'O grm. per diem, the usual average
being 0'7 grm. per diem. But it is much increased by a
vegetable diet, especially after a large consumption of fruit and
vegetables. Hippuric acid is plentiful in the urine of herbivora,
and to a large extent replaces uric acid, which is present only in
a small amount. These facts show clearly that the chief part of
the hippuric acid of the urine is of alimentary origin, because
the food-stuffs contain either benzoic acid itself or substances
which are capable of conversion, in the intestinal tube or within
the tissues, into this acid.
In 1824 Wohler discovered that it is only necessary to mix
benzoic acid with the food of any mammal in order to see it
reappear in the urine in the form of hippuric acid. This discovery,
which was confirmed by subsequent observers, was the first well-
established instance of synthesis within the animal body. In 1876
Schmiedeberg and Bunge made an exhaustive study of the
question in which organ the synthesis that gave rise to hippuric
acid took place. They excluded the possibility of its being the
liver, because in dehepatised frogs the subcutaneous injection of
benzoic acid, or benzoic acid and glycocoll, gave rise to the forma-
tion of hippuric acid. They found that in dogs the organs which
394 PHYSIOLOGY CHAP.
synthetise hippuric acid are exclusively the kidneys, for when
these organs are excised, and benzoic acid and glycocoll injected
into the blood, the animal then being killed after 3-4 hours, there is
no trace of hippuric acid, either in the blood, or in the liver or
muscles, but, on the contrary, free benzoic acid is found. To this
negative proof that the kidneys formed hippuric acid by synthesis,
they added positive proof, by establishing artificial circulation
with defibrinated blood, to which they added glycocoll and benzoic
acid, in the freshly excised kidneys of a dog. Hippuric acid was
found to be present both in the blood that left the kidneys and
ill the fluid that escaped from the ureters. The phenomenon
occurred equally when the blood was warmed to the temperature of
the body, and when it was cold. If benzoic acid only was added
to the blood, the amount of hippuric acid formed was less.
The synthesis also took place partially when the kidney
was broken up into small pieces, steeped in the extracted blood to
which benzoic acid and glycocoll had been added, and then agitated
(Kochs) ; but if the kidney is reduced to a homogeneous pulp, so
as to exhaust the vitality of all its cells, or if a kidney excised
several hours previously is used, there will be no trace of hippuric
acid (Schmiedeberg and Bunge). It is clear that this synthesis
does not depend on specific chemical compounds in the renal
tissue, but on the metabolic activity of the surviving cells of the
excised kidney.
No hippuric acid is formed when serum that has been entirely
deprived of corpuscles by the centrifuge is employed, instead of
circulating defibrinated blood containing benzoic acid and glyco-
coll in the kidney. The participation of the blood corpuscles is,
therefore, indispensable to the synthesis effected by the kidneys,
probably because they supply the oxygen. This is proved by the
fact that the synthesis also fails when the artificially circulated
blood has been previously saturated with carbon monoxide.
If in dogs the kidneys alone have the power of effecting the
synthesis of hippuric acid, the same cannot be affirmed of other
animals. In fact, Schmiedeberg and Bunge saw a formation of
hippuric acid in frogs after the extirpation of the kidneys:
Salomon found hippuric acid in the blood, muscles, and liver of the
rabbit, after nephrectomy, when benzoic acid was introduced.
We do not know whether the synthesis of hippuric acid takes
place in man exclusively by the kidneys, as in dogs, or by means
of other tissues also, as in rabbits. We only know that in renal
diseases in which there is a conspicuous degeneration of the
epithelia, a lesser amount of hippuric acid is formed, and if benzoic
acid be administered in these cases some of it reappears as such in
the urine (Stokvis, Kronecker).
If benzoic acid is injected into birds, it does not, according to
Jaffe (1877), reappear as hippuric acid, but in combination with
vii KATABOLIC CONSTITUENTS OF URINE 395
another compound, which he terms ornithine, and which, with
benzoic acid, forms oriiithuric acid.
In his Text-book Hoppe-Seyler cites a whole series of com-
pounds similar to hippuric acid, in which the benzoic acid is
replaced by other aromatic bodies, e.g. salicylic, toluic, anisic,
cumin ic, and other acids, which with glycocoll give rise to sali-
cyluric, toluylisuric, anisuric, cuminuric acid, etc. According to
Salkowski, phenaceturic acid is found in the urine of the horse,
and perhaps in small traces in that of man also. It arises from
the combination of glycocoll with phenylacetic acid.
Among the aromatic substances of normal urine, the ethereal or
conjugated sulphates are more important from the physiological
standpoint. Stiideler in 1861, while distilling the urine of ox and
man, discovered the presence of phenol or carbolic acid. Buliginski,
and at a later date Hoppe-Seyler, found that the phenol of the
urine present is not in the free state, but bound up with an acid
from which it separates on distillation. Baumann (1876) first
discovered that phenol forms an ethereal compound with the
radical of sulphuric acid (HSO3), and that in the urine several
potassium salts of ethereal sulphates were present, the principal
being those containing phenol, cresol, catechol or pyrocatechin,
indoxyl, and scatoxyl. The latter are formed from indole and
scatole by oxidation, and .they form with sulphuric acid indoxyl-
and scatoxyl-sulphuric acid.
In the urine of herbivora the group of ethereal sulphates is
more abundant than in that of the carnivora or man, but it is
present in small quantities in the urine of all animals.
The ethereal sulphates present in the urine of herbivora are
undoubtedly formed from the aromatic substances contained in the
vegetable food : they are formed in the intestine from the aromatic
compounds by putrefactive processes ; after absorption they enter
the circulation, combine with the sulphuric acid radicle, and are
eliminated (in the form of potassium salts) as conjugated
sulphates.
In dogs and man the aromatic substances introduced with the
food are small in quantity ; they are excreted as ethereal sulphates
and give a measure of the putrefactive processes carried on in the
intestine. When intestinal putrefaction was arrested in dogs by
strong doses of calomel or iodoform, Baurnann and Morax observed
a total disappearance of ethereal sulphates from the urine. In
man it is difficult to obtain this result, since too strong a dose of
the disinfectant would be required, but it is possible to reduce the
amount of ethereal sulphates considerably by other means.
Rovighi's experiments (1891) are interesting from the clinical
point of view. He found the elimination of ethereal sulphates to
be relatively higher in the daytime than at night; ingestion of
fluids increases excretion of aromatic bodies as compared with
396 PHYSIOLOGY CHAP.
sulphates in the urine ; both the total sulphuric acid and the
ethereal sulphates are scanty in children, while they are abundant
in older people. In other experiments on himself, on his patients,
and on dogs, Rovighi tried to determine which substances were
most effective in diminishing the putrefactive processes of the
intestine, and therewith, the ethereal sulphates of the urine. His
conclusions are as follows : —
(a) The group of terpenes and camphor, especially oil of
turpentine and camphor, administered in large doses to dogs,
produced a considerable diminution in the aromatic products of
intestinal putrefaction, which lasted for some time.
(&) The same substance, introduced by the mouth or per
rectum, acted less efficaciously on man.
(c) The use of Carlsbad and Marienbad salts increases the
elimination of ethereal sulphates during the first few days, but
subsequently has the opposite effect, which is more marked in
proportion as the previous intestinal disturbances had been
conspicuous.
(d) Milk fermented with kefir taken in an amount of 1| litres
a day is effective in checking intestinal putrefaction, owing mainly
to its lactic acid content.
The fact that saline purgatives and mineral waters (including
those in which the main content is sodium chloride) diminish the
putrefactive processes of the intestine and reduce the amount of
ethereal sulphates in the urine, was afterwards confirmed by
Ewald of Berlin, by Fedeli and Casciani, and others. .
A relative increase in the ethereal sulphates of the urine has
been noted (Coggi), not only in disorders of the intestine, but also
in chronic suppurative lung diseases, the putrefactive processes in
this case arising from the pulmonary bacteria.
According to Baumann the synthesis of ethereal sulphates
probably takes place in the liver. Kochs observed a partis
synthesis of phenol and sodium sulphate, on adding them to blc
which was left to digest with the liver and kidneys.
Eeale further found that if phenol is injected into dogs, aft
tying all the hepatic vessels (an operation which they only survive
for 2 to 4 hours) no phenyl sulphate of potassium is found in the
urine or the bladder, which proves that under these conditions no
other tissue or organ is able to synthetise the ethereal sulphates.
The liver thus seems to be the only organ which performs thie
synthesis.
The ratio between the ethereal sulphates and the total sulphates
of human urine is on an average, according to a number of
analyses, 1 : 10. In the diseases in which the putrefactive
processes of the intestine are increased, the value of this quotient
also increases in proportion. According to Hoppe-Seyler, this is
regularly the case : (a) in peritonitis and intestinal tuberculosis,
vii KATABOLIC CONSTITUENTS OF UKINE 397
in which absorption of the products of intestinal digestion is
defective ; (&) in gastric disease, which causes a block of food in
the stomach, and thus obstructs the fermentative processes ; (c) also
in diseases localised outside the digestive canal (cystitis, abscesses,
suppurative peritonitis), in which putrefactive processes develop.
It is remarkable that in abdominal typhoid and in cases of
simple intestinal constriction, the ethereal sulphates of the urine
do not increase to any large extent.
VI. The urine collected under normal conditions, and still
more in different pathological states, is rich in pigments, and sub-
stances readily converted into pigments and therefore known as
cliromogens. When examined in the spectroscope, however, normal
urine exhibits no special absorption bands, but only a simple and
partially diffused absorption, which varies in intensity in the
different regions of the spectrum. It increases in the direction of
red to violet, but in a different degree in different urines (Vierordt),
showing that the quantity and number of the urinary pigments
may vary, even under physiological conditions.
Few of the pigments detected by different workers have been
obtained in quantities sufficient for chemical analysis : so that the
distinct chemical individuality of many of them may be doubted,
the more so as they are highly unstable, and readily undergo
' decomposition on treatment with strong reagents. The better-
known pigments are urochrome and urobilin, the first being that
which 'gives the urine its normal colour, while the second is
•usually present only in the form of its chromogen in fresh urine,
so that it cannot be held (as many claim) to be a primary urinary
pigment.
Urochrome, isolated by Thudichum (1864) in an impure state,
mixed with other pigments, was obtained as a distinct chemical
substance by Garrod (1894). He showed it to be a nitrogenous
but iron-free substance, which gives the xanthoproteic reaction,
and must therefore be regarded as an aromatic body. Although
in the dry state it is amorphous and brown in colour, its aqueous
solutions have, according to their concentration, the normal hue of
urine in its various shades of clear yellow to orange and brown.
Examined through the spectroscope it shows no special absorption
bands, but absorbs the light diffusely, with increasing intensity
from red to violet, like normal urine as a whole. It is therefore
evident that urochrome is the principal pigment of normal urine.
The relationship between urochrome and urobilin is shown by
their reciprocal conversion, on treating the former with a reducing
and the latter with an oxidising agent. Garrod (1897) found in
fact that the alcoholic solutions of urochrome treated with pure
aldehyde give a pigment that shows all the reactions of urobilin.
Riva (1896), on treating the latter with permanganate of potash,
obtained a pigment which seems identical with urochrome.
398 PHYSIOLOGY CHAP.
Urobilin was separated from the urine of fever-patients by
Jaffe (1868), but in normal urine he found a chromogen which is
readily converted into urobiliu, not only by the action of acids, but
also by mere exposure of the urine to air and light. On spectro-
scopic examination the acid solutions of urobilin show an absorp-
tion band which corresponds with the transition from 'green to
blue, more precisely between b and F. (See Vol. I. Fig. 35, p. 110.)
Maly's hydrobilirubin gives a very similar spectrum, as also
the stercobilin found by Vanlair and Masius in the faeces. It is
therefore not improbable that urobilin is identical with hydro-
bilirubin and stercobilin. But they differ in other respects, and
the question has not yet been decided.
The amount of urobilin in normal urine after the whole of the
urobilinogen has been converted into pigment varies, according to
Saillet, from 30 to 130 mgrms. per diem. According to Arcangeli
and Cavazza, under normal conditions, 65 mgrms. urobilin are ob-
tained on an average from man, and 60 mgrms. from woman.
It increases considerably in fevers, in many infectious diseases, in
all the anaemias accompanied by exaggerated haemolytic processes,
in many hepatic diseases, etc.
Urobilinogen is undoubtedly derived from blood pigment and
the bile pigments, particularly from bilirubin. It is certain that
the chief part of the urobilin and urobilinogen of the urine
originates in the intestine from the bile pigments, in consequence
of the fermentative processes due to intestinal microbes. The
following facts can be adduced in support of this theory : —
(a) Urobilinuria occurs when the putrefactive processes of the
intestine are exaggerated (Harley).
(&) Urobilin is absent in the urine of the newborn before any
bacteria penetrate the intestine (Fr. Miiller), while stercobilin is
at the same time absent from the faeces (Eiva).
(c) Urobilin is absent in adults after complete occlusion of the
bile passages, and makes its appearance again when the flow of
bile to the intestine recommences (Beck, Eiva, and Zoja).
(d) On estimating the urobilin and urobilinogen of the urine
and the faeces, there is in every case a certain proportionalitj
(Kiva).
The formation of urobilinogen from bilirubin in the intestine
does not take place by simple hydrolysis, as Maly believed froi
his work on hydrobilirubin, but by a more profound metamorphosis
of the bilirubin molecule. This loses half its nitrogen, as shown
by Garrod and Hopkins from quantitative elementary analyses of
the elements of these substances, as obtained by various meai
and from various sources.
The most favourable conditions for the formation of urobilinogei
from bilirubin occur in the normal course of the functions of the
intestine. Nearly the whole of the urobilinogen formed in the
vii KATABOLIC CONSTITUENTS OF UEINE 399
intestine is eliminated with the faeces, the remainder is absorbed
and carried by the portal vein to the liver, where it is partially
poured out again into the intestine with the bile, partially traverses
the hepatic veins and is excreted with the urine (Kiva).
It is possible from daily determinations of the quantitative
fluctuations of the urobilinogen content of the urine and faeces,
together with estimations of the variations in the haemoglobin
content and number of erythrocytes in the blood, to calculate the
value of the haemoglobin exchange, i.e. the extent to which the
haemoglobin is destroyed and formed again (Zoja). The bilinogen
content of the urine and faeces increases after hard muscular work,
in fevers, and, generally speaking, with exaggerated haemolysis,
and diminishes during convalescence from febrile maladies and
in chlorosis.
According to Riva's interesting studies, the urobilinogenesis is
in strict relation with the quantity of bilirubin secreted by the
liver-cells. Estimation of the urobilin content of the urine and
faeces therefore gives a criterion of the normal or more or less
degenerated hepatic cells. The persistence of the urobilin (and
still more its increase) must' indicate a favourable prognosis, even
in serious cases of hepatic disease. This theory of Riva is confirmed
by observing the way in which the formation of urobilinogen alters
in the course of intoxication by phosphorus and nitric acid.
The possibility is not, however, excluded of a certain amount
of urobilin and its chromogen being formed, along with other bile
pigments, by the metabolic activity of the hepatic cells (Hayeni),
and also by the reducing action exerted on the bile pigments by
the various tissues, especially the kidneys (Quincke, Kiener,
Engel, Mya). This view, which assumes in addition to the
intestinal, a hepatic and renal origin for urobilinogen, is supported
by the fact that in the descending phase of cholaemia bilirubin
alone is found in the blood, urobilin alone in the urine, which can
be explained on the assumption that the first is converted by the
action of the renal epithelia into the second.
Urobilin must not be confounded with the pigment that pro-
duces the dull red colour of the urate sediment. This comes from
the uroerytlirin present in minute quantities in normal urine, to
a larger extent in fibrile urine. Uroerythrin has specific chemical
and spectroscopic characteristics which differ from those of
urobilin. Probably it is contained in the urine as a sodium salt
in combination with the urates.
The genesis of uroerythrin and its relations with Garrod's
urochrome and urobilin are unknown. According to Riva, Prima-
vera and Reale, uroerythrin is found particularly in diseases of
the liver (cirrhosis), and generally in all morbid conditions in
which urobilinuria is present. It is probable from clinical observa-
tions that the presence of uroerythrin connotes some alteration of
400 PHYSIOLOGY CHAP.
the hepatic cells (even if slight and fugitive), such as usually
arises from gastro-enteric disorders.
Of the chroniogens contained in the urine, the most important
from its physiological significance is undoubtedly indican, which
is readily oxidised, and gives rise to indigo-blue and its isomer
indigo-red. Jaffe was the first who recognised, by special experi-
ments with diet, that indole is the mother-substance of the
indican of the urine. Baumann proved that indoxyl is formed
by oxidation of indole, and that it is, as we have seen, normally
present in urine in combination with sulphuric acid and potassium
in the form of potassium indoxyl- sulphate (indican). From this
compound the indoxyl resists oxidation : it is liberated by hydrolysis
with acid, and on oxidation to indigo the urine may be stained
blue or red.
The practical importance of the indican reaction of the urine
rests on the fact that indole, its mother-substance, is the most
characteristic product of the protein putrefaction that takes place
in the intestine. From the relative indican content of the urine
we can therefore make an approximate estimation of the putre-
factive processes in the intestine. Quantitative estimation of the
whole of the ethereal sulphates, however, gives a more exact
criterion of the degree and intensity of intestinal putrefaction,
because indole is not the only aromatic body present in the urine.
VII. Small quantities of non-nitrogenous organic acids are
very frequently present in normal urine, among which we must
confine ourselves to noting oxalic acid, lactic acid, and various
fatty acids.
Although not constant (Neubauer), the presence of oxalic
acid in the form of calcium oxalate in the urine is held to be
normal. It crystallises readily a few hours after the urine has
been passed, probably in consequence of an acid fermentation.
Normally it is held in solution by the acid sodium phosphate.
According to Fiirbringer the oxalic acid content of human
urine fluctuates from a hardly perceptible trace to 20 mgrms. per
diem ; according to Schultzen, on the contrary, it may amount to
10 cgrms. per diem. In the urine of certain animals (horses, pigs)
it is found in much higher quantities.
Part of the oxalic acid of the urine is undoubtedly alimentary
in origin. Many fruits and vegetables, as well as herbage, contain
oxalic acid, which resists oxidation in the body, and is largely
excreted again in the urine (sorrel, spinach, asparagus, grapes,
apples, rhubarb, gentian, etc.). Still it is a well-established fact
that oxalic acid can be detected in the dog's urine independent of
vegetable 'food during an exclusive diet of meat and fat (Mills).
The katabolic processes of the tissues can thus give rise to a
formation of oxalic acid. The specific conditions of this process
are not yet known. According to some interesting observations
vii KATABOLIC CONSTITUENTS OF UKINE 401
of Gaglio, delayed circulation is a condition favourable to the
formation of oxalic acid. In fact, if a frog is immobilised by
curare (Vulpian) or other means (Gaglio), calcium oxalate appears
in the urine. Any artificial diminution of the oxidative processes,
again, promotes formation of oxalic acid. In dogs Keale and
Boeri observed this on obstructing the respiration; Terray on
diminishing by half the oxygen of the inspired air. In pathological
conditions oxaluria has been observed in fevers, in illnesses accom-
panied with serious respiratory disturbances, or grave depressions
of the nervous system, and above all when general metabolism is
sluggish.
Increase of oxalic acid is often associated with increase of uric
acid. With artificial introduction of uric acid and urates, again,
Wohler and Frerichs succeeded in obtaining an increase of calcium
oxalate in the urine. Since uric acid splits under the action of
ozone into urea, oxalic acid and allantoin (Gorup-Besanez), it is
not improbable that a similar decomposition takes place in the
body.
Lactic acid was formerly regarded as one of the normal con-
stituents of urine (Berzeli us) ; later on, this theory was held to be
fallacious (Liebig). Recent observations of Hess, however, make
it probable that a trace of lactic acid is normally present in the
urine. Spiro's researches show that after hard muscular work the
amount of lactic acid combined with bases increases conspicuously
in the urine. This fact was confirmed by Colasanti and Moscatelli,
who found a large amount of paralactic acid in the urine of
soldiers after a 24 kilometres march. The same phenomenon was
subsequently confirmed by Vicarelli in the urine of women in
childbirth, after a difficult delivery.
Lactic acid appears as a consequence of various intoxications ;
in poisoning by phosphorus (Schultzen and Eiess), carbonic oxide
(Miinzer and Palma), curare, morphine, cocaine, amyl nitrite,
veratrine (Araki), and, generally speaking, under all conditions
which, by obstructing the respiratory gas exchanges, weaken the
processes of oxidation. After extirpation of the liver in geese,
Minkowski noted lactic acid in the urine. The same was con-
firmed by Nebelthan for frogs. Zillessen evoked the same
phenomenon in dogs, by simple Legation of the hepatic artery,
Taken as a whole, these facts make it probable that the
formation of lactic acid is associated with a deficit or check in the
oxidative processes in the body.
Normal urine further contains small quantities of volatile
fatty acids, specially acetic, formic, propionic, and butyric acid
(v. Jaksch). According to Jaksch the daily amount of these does
not exceed 8-9 mgrms., but it increases to a marked extent on
a farinaceous diet, and in pathological conditions, in fevers in
general, in certain hepatic diseases, in diabetes. In all probability
VOL. ii 2 D
402 PHYSIOLOGY CHAP.
these originate in the bacterial processes of fermentation and
putrefaction which the proteins and carbohydrates undergo in the
intestine. The fatty acids of low molecular weight are probably
oxidised after their absorption in the blood, while those of higher
molecular weight undergo incomplete oxidation only, and are
eliminated partly by the lungs, partly by the kidneys. They are
more abundant in the urine of the herbivora than in that of
carnivora.
VIII. The question whether normal urine contains sugar or
not has been much discussed. It is difficult to clear up this point
because certain substances in the urine have, in common with
sugar, the property of reducing the oxides of copper and mercury
in alkaline solution ; such are uric acid, hippuric acid, creatinine,
pyrocatechin. These substances are not, however, like sugar liable
to alcoholic fermentation, which is constantly observed when
beer yeast is added to urine (Abeles). Nearly every one iiow
believes in the view originally put forward by Briicke, that urine
normally contains traces of glucose or dextrose.
A considerable amount of lactose is present in the urine of
women during lactation (Blot, Hofmeister, and others). The
physiological and pathological conditions under which the sugar of
the urine can be increased temporarily (glycosuria) or permanently
(diabetes mellitus), have already been treated at length (Chapter V.
p. 314 et_seq.').
According to Landwehr's researches, a carbohydrate similar
dextrin, and non-fermentable, is always present in normal urine :
this he termed animal gum. It can be isolated by means of it
property of forming an insoluble compound with copper. Whei
boiled with acids, animal gum gives rise to a reducing substanc
(probably a sugar) which increases the total reducing power of
the urine. Wedenski and Baisch confirmed the observations of
Landwehr. It is probable that the mother-substance of animal
gum is mucin, the chief constituent of the mucus secreted by the
epithelia that line the urinary passages, which under normal
conditions is present in small quantities in the urine.
According to v. Jaksch, normal urine always contains a small
quantity of acetone or dimetliylketone (C3H60), a compound closely
allied to the alcohols, which was first discovered in large quantities
in diabetic urine by Fetters (1857) and Kaulisch (1860).
The presence of acetone in normal urine was questioned l>y
Albertoni, le Nobel, and Moscatelli ; but it has been confirmed by
others — in Italy by Boeri, who regularly found 12-15 mgrms. per
diem under physiological conditions. It appears in considerable
quantities in diabetics, and under various morbid conditions
accompanied by fever ; in different gastro - intestinal affections ;
in many pathological or experimental lesions of the nervou
system, in various exogenous or endogenous intoxications, '
vii KATABOLIC CONSTITUENTS OF UEINE 403
carcinoma, in various anaemic and leucaemia conditions. According
to Boeri and Reale, acetonuria is generally induced by the condi-
tion which causes oxalur-ia, and an excessive formation of acids in
the body, viz. diminished gas-exchanges, and depression of the
oxidising processes in the tissues. In fact, on obstructing
pulmonary ventilation in dogs by applying Sayre's jacket to the
thorax, they obtained marked modifications in the katabolic tissue-
processes, characterised by increased consumption of proteins,
excessive formation of acids, oxaluria, and acetonuria, with
corresponding increase of ammonia in the urine.
Urine also contains a derivative of glucose, which has the
characteristics of the aldehydes and acids, and can be readily
interchanged with sugar on account of its marked reducing power.
This is glycuronic acid (CGH1004). In normal urine there is,
according to Schmiedeberg, a small quantity of glycuronic acid
combined with phenol, indoxyl, and scatoxyl with which it forms
glycuronic esters, which readily split up when treated with
mineral acids.
On the exhibition of certain poisons or drugs, the quantity of
glycuronic acid in the urine increases considerably. This is seen
in chloroform narcosis ; after the use of chloral, camphor, morphine,
curare, etc. The apparent glycosuria induced by these substances
is due to the glycuronic esters, and should therefore be termed
glycuronuria.
Addition of beer yeast to the urine does not cause any marked
alcoholic fermentation, such as invariably appears in glycosuria.
The glycuronuria due to drugs is transitory and has only a
clinical interest. The rare cases of spontaneous glycuronuria, on
the contrary, i.e. such as are not produced by poisons or drugs,
are interesting not because they represent any dangerous alteration
in the katabolic tissue processes like diabetes, but because they
elucidate the physiological problem of the origin of glycuronic
acid. For the present we must confine ourselves to the chemical
researches by which glycuronic acid has been obtained from sugar ;
and from which we learn that this acid is an intermediate product
of carbohydrate metabolism. It probably appears in the urine
when it escapes complete oxidation, by combining with the
aromatic bodies or with other substances foreign to the ordinary
diet or the normal katabolism of the tissues. In the same way
glycocoll escapes oxidation by combining with the benzoic acid,
and appears in the urine in the form of hippuric acid.
Pentoses also can be isolated in the urine, particularly after
the ingestion of fruits that contain them (alimentary pentosuria).
A spontaneous pentosuria has also been noted, without any
apparent external cause (Salkowski and Jastrowitz, 1892).
Luzzatto, who with Keale has specially occupied himself with
pentosuria in Italy, was the first to isolate an active pentose
404 PHYSIOLOGY «HAP.
(l-arabinose) from a pentosuric urine. In the very rare cases so
far described, there is a benign anomaly of metabolism which may
be easily confused with diabetes, if the special methods for
detecting pentose are not applied to the analysis of the urine.
IX. The urine of normal individuals yields in the great
majority of cases no trace of protein. This fact is beyond con-
troversy, as all the most reliable authorities agree on it. There is,
however, no ground for assuming that albuminuria is in every
case a pathological phenomenon. Under special conditions even
perfectly healthy individuals exhibit a transitory albuminuria
which, even if accidental or abnormal, cannot be regarded as
morbid.
We saw in Chapter V. p. 287, that a transitory albuminuria
makes its appearance after the consumption of a large amount of
egg -albumin. Landois stated that he had seen albuminuria
in a man 4-10 hours after the ingestion of the raw, salted
whites of 14-20 eggs. The albumin content of the urine increased
progressively to the end of the third day, after which it began to
decrease, and disappeared altogether by the fifth day. The same
phenomenon occurs on the direct injection of ovalbumin into the
circulation (Stokes, Lehmann, Verdelli, and Gabbi).
Some admit a slight transitory albuminuria, independent of
any renal lesion or excessive consumption of egg-albumin, when-
ever the amount of protein in the blood plasma is abnormal,
either from excessive protein alimentation, or from reabsorption
when the lacteal function is suspended (v. Bamberger, Posner,
Hawkins). This form of transitory albuminuria is termed
haematogenous.
After excessive muscular work, again, a slight albuminuria
described as physiological or functional, can be detected (Leube,
Dukes, Fiirbringer, G. Marcacci).
Leube investigated the urine -of 119 soldiers, both in the
morning before they were drilled, and in the evening after com-
plicated and fatiguing marches. The morning urine of five
individuals yielded albumin, i.e. in 4'2 per cent ; in the evening
it was present in 19 individuals, i.e. in 16 per cent. In no
instance did the amount of albumin exceed O'l per cent.
Capitan's researches on soldiers of 2.1-25, as well as on children
from 1 to 8 years of age, confirmed the fact that physiological
albuminuria is a very common phenomenon. Not unlike this is
the albuminuria that has been observed after the convulsive
spasms excited by strychnine, or in man after epileptic attacks
(Huppert).
Transitory albuminuria may occur also in consequence of a
rapid rise in blood pressure in the vascular district of the kidneys,
e.g. after cold baths (Lassar, Johnson, Hawkins). Johnson's cases
were young, healthy students, who after 15 minutes to 1 hour's
vii KATABOLIC CONSTITUENTS OF URINE 405
immersion in cold water, complained of fatigue and headache,
followed by slight albuminuria of short duration.
Albuminuria can be experimentally produced in animals by
abnormal increase of blood pressure in the vascular parts of the
kidneys. We shall speak of this in the next chapter, in discussing
the secretion of urine.
In almost all cases of spontaneous or experimental albuminuria,
serum-globulin is associated with serum-albumin in the urine, in
proportions that vary considerably from 8-60 per cent of the total
coagulum (Hammarsten, Hoffmann, Patella, Czatary). Serum-
globulin may be present without serum -albumin, or vice versa.
In true nephritis (Bright's disease'] the so-called urinary casts are
invariably present in urine, showing that the fibrinogen of the
blood plasma is also thrown out by the kidneys, and suddenly
converted into fibrin, which takes the cylindrical form of the renal
canaliculi. The total amount of protein eliminated by the kidneys
rarely exceeds 1 per cent, but may, in certain cases, amount to
4 per cent (Hoppe-Seyler).
The cases of Jiaematuria, or admixture of blood in toto with
urine, or of the blood pigment only (haemoglobinuria or methaemo-
globinuria), belong exclusively to pathology.
Enzymes may also be included among the proteins of the
urine, pepsin (Briicke, 1861) and the diastatic ferment (Cohnheim,
1863) being constantly present in normal urine.
Pepsin is abundant in the urine passed in the morning before
a meal (Sahli, Mees), scanty in the urine secreted in the first hours
after a meal (Sahli, Gehring, Hoffmann). • After prolonged fasting
there is no trace of it, but after consumption of food it appears
again abundantly (Leo, Senator). In disease it seems to diminish,
but observations on this point are at variance, so that the fact
cannot be used in diagnosis (Leo, Wasilewski, Mya and Bonfanti,
Stadelmann).
The presence of trypsin in urine is denied by Sahli, regarded
by others as inconstant. Bendersky, however, always detected a
substance in normal urine which dissolved fibrin in alkaline
solution. This fact was confirmed in our laboratory by Tarulli
in the urine passed before a meal. The substance disappears
during digestion, and subsequently reappears.
The diastatic enzyme is constant in the urine of man and
rabbits. It increases after a meal, and diminishes in the night-
urine, and during abstinence (Gehring, Hoffmann).
Till recently it was assumed that these digestive enzymes
were included among the specific products of the gastric,
pancreatic, and salivary secretions, which, after fulfilling their
. digestive functions in the gastro-intestinal canal, are reabsorbed
previous to decomposition, brought into the circulation, and
eliminated by the kidneys. At present the tendency is rather to
406 PHYSIOLOGY CHAP.
conclude that the ferments of the urine are derived from the
intracellular ferments which have been demonstrated within
every organ, and which give rise to the so-called autolytic cleavage
products (Salkowski. See Vol. I. p. 34).
Matthes attempted to solve the question of the origin of the
enzymes of the urine by experiment (1903-4). On analysing the
urine of dogs from which he had previously removed the whole of
the stomach, or pancreas, he saw that in the first case no pepsin
could be detected in the urine; while after removal of the pancreas
ferments were still present, which were able to split up protein in
alkaline solution. This led him to conclude that the proteolytic
enzyme of the urine which acts in an acid medium, is reabsorbed
pepsin, and not an autolytic ferment. On the other hand, even
when the possibility of trypsin reabsorption is excluded, proteolytic
cleavage can take place in an alkaline medium ; this is evidently
due to ferments eliminated with the urine, which must be autoch-
thonous in the different tissues of the body.
X. The inorganic constituents of urine are chlorides, carbonates,
sulphates, and phosphates, the bases of which are represented by
soda, potash, ammonia, lime, and magnesia. Small quantities of
fluorine, silicic acid, and iron are also found in urine. The total
quantity of salts in the urine fluctuates from 9 to 25 grms. per diem.
The salt most abundantly present in the urine is sodium
chloride, with which are associated small amounts of potassium
chloride and traces of calcium and magnesium chloride. 6-8 grms.
chlorine can be found in the urine in one day, which correspond to
10-13 grms. sodium chloride. The whole of the salt used as a
condiment reappears in the urine partly on the same, partly on
the next day (Dehn). A small proportion of it is decomposed by
the glands of the fundus of the stomach in the formation of hydro-
chloric acid, and is then regenerated in the intestine by the sodium
carbonate of the succus entericus. (See Chapter IV. p. 222.)
The sodium chloride of the urine increases after an abundant
meal, and diminishes in the night hours. It increases after copious
draughts of water. It diminishes temporarily after an abundant
secretion of gastric juice. It increases after inhalation of chloro-
form, and not after taking chloral (v. Mering), although both these
are compounds of chlorine. Injection of potassium salts increases
the elimination of sodium chloride (Bunge).
It must not be thought that the whole of the sodium chloride
remains in a free state dissolved in the plasma, serving merely as
a vehicle for the metabolic exchanges of the tissues. Part of it is
chemically combined with the organic molecules of the bioplasm,
and enters, as it were, into the chain of its metabolic processes — is
in short, a true mineral aliment. In proof of this it is only
necessary to consider how the total chlorine content of the urine
varies during and after fasting. We ourselves, in the case of
vii KATABOLIC CONSTITUENTS OF UKINE 407
Succi, as also I. Munk on Cetti, observed a progressive diminution
of the chlorine content from the commencement to the end of the
fast. During inanition, when the plasma and tissues are very
poor in sodium chloride, ingestion of this salt produces no corre-
sponding rise in its excretion. On resuming the normal diet a
considerable amount of the salt given with the food is retained for
two or three days.
Pathological observations support these facts. In febrile
maladies in general, especially in pneumonia, rheumatic arthritis,
and typhoid, there is a very marked diminution in the sodium
chloride excretion by the urine (hypochloruria). According to
Salkowski this is not merely the result of the decreased consumption
of salted foods, but is a true retention of chlorine in the body. In
fact, sodium chloride excretion rises again without ingestion of
food, as soon as the crisis of the illness is over. In one case of
pneumonia, the sodium chloride excreted fell to 1-1-6 grm. per
diem, and rose again after the crisis to V-87 grms., and on the
next day to 16 '18 grms. This fact cannot be explained simply
by reabsorption of the exudate, the molecular concentration of
which is always isotonic with blood plasma (Winter and others) —
one of the most important functions of the sodium chloride in the
blood being to maintain equilibrium in the osmotic pressure of the
tissue fluids.
The sulphuric acid excreted in the urine, either in the form of
alkaline sulphates or combined with the aromatic products in the
form of ethereal sulphates, amounts as a whole in adults, with a
mixed diet, to T5-3 grms. per diem calculated as S03 (Flirbringer
and Neubauer). As a rule, the amount of sulphates introduced
with the food is scanty, and even when abundantly supplied in
the form of magnesium or sodium sulphate the greater part of
these salts are eliminated by the intestine, on which they act as a
cathartic. The sulphuric acid of the urine thus originates almost
exclusively from the oxidation of the sulphur of the proteins
introduced with the food, or from the tissue protein consumed.
The variations of the sulphuric acid in the urine are therefore
almost parallel with those of the urea, both being decomposition
products of protein.
The amount of sulphuric acid combined with the aromatic
ethers is on an average TV the total sulphuric acid, but this ratio
is subject to many pronounced oscillations according to the nature
of the diet and the varying intensity of the putrefactive processes
of the intestine (supra, p. 395 et seq.*).
The whole of the sulphur contained in the urine does not
appear as sulphuric acid : part of it is present in the form of
organic compounds of which some only are known to us. Salkowski
gives the name of neutral sulphur .to these, to distinguish them
from the preceding or acid sulphur. Neutral sulphur constitutes
408 PHYSIOLOGY CHAP.
about 20 per cent of the total sulphur. It consists partly of the
sulphocyanide^ of the saliva, partly of the taurine of the bile, partly
of compounds homologous with cystine.
Phosphoric acid is present in normal urine, in the form of
alkaline phosphates (mostly sodium, a little potassium) and of
earthy phosphates (chiefly calcium, a very little magnesium).
The acidity of the urine, as stated, depends principally on the
monobasic phosphates of sodium and calcium, the so-called acid
phosphates. When the urine is neutral, part of the monobasic are
replaced by dibasic phosphates. When, lastly, the urine is alkaline,
a more or less considerable part of the phosphates is found in the
form of tribasic phosphate, sodium, calcium, magnesium. Lastly,
it should be noted that part of the phosphoric acid in the urine is
combined with ammonia.
The phosphoric acid of the urine comes partly from the food,
partly from the decomposition of the organic phosphorus com-
pounds of the tissues. Meat, milk, cereals, vegetables, which
represent the principal food -stuffs, are more or less rich in
phosphates. Part, however, of these alimentary phosphates
(particularly the phosphates of calcium and magnesium) are not
absorbed by the intestine, but pass out unaltered in the faeces.
In fact the urine of herbivora is comparatively poor in phos-
phates, although earthy phosphates abound in their diet. But
the tissues are also more or less rich in phosphates, the bones
especially so in the form of calcium and magnesium phosphate.
There is, further, a group of organic phosphorus compounds, in
which are included the nuclein, which forms the chromatin of cell
nuclei, lecithin, which is most plentiful in the nervous system, and
jecorin, found principally in the liver. All these substances are
able by oxidation of the phosphorus to form phosphoric acid which
appears in the urine.
The amount of phosphoric acid excreted daily fluctuat
between 2'5 and 3'5 grms. The earthy phosphates represent
about half the total phosphates. In general it may be stated that
the fluctuations of the phosphorus content of the urine correspond
with the fluctuations of the nitrogen content. This is especially
shown when the subject experimented on is kept on a constant
diet, so that the amount of phosphates and inorganic phosphorv
compounds introduced does not vary perceptibly. On a normal
mixed diet, the average ratio between the phosphorus and nitrogen
content of the urine is as 1 : 17'45, i.e. for one gramme of phos-
phorus there are 17'45 grammes nitrogen in the urine. During
Succi's 30 days' fast at Florence, we found that the quotient p w«
always lower than 17'45, which means that during inanition the
excretion of phosphorus increases considerably in comparison with
the excretion of nitrogen. I. Munk made the same observation
vii KATABOLIC CONSTITUENTS OF UEINE 409
in Cetti's 10 days' fast, and explained it logically on the assumption
that during inanition the bone tissues, which are rich in phosphates
and poor in nitrogenous substances, are used up. Evidence in
favour of this assumption is afforded by the fact that in fasting
the amount of calcium and magnesium, which are the bases of the
bone phosphates, also increase in the urine. The excretion of
phosphates in fever, which is almost always accompanied by more
or less accentuated phenomena of inanition, should be further
investigated, in view of this important fact observed during
complete abstinence.
According to Ott's researches the influence of diet appears
plainly in the daily curve of the total elimination of phosphates,
which rises and reaches its maximum in the hours that succeed
the principal meal, and falls again in the night hours, reaching its
minimum in the hours that precede a meal.
The carbonic acid of the urine occurs partly in a free state,
partly combined as carbonates, and bicarbonates with soda, lime,
magnesia, and ammonia, which are specially abundant in the
fresh, alkaline urine of herbivora.
Free carbonic acid, according to Planer, is present in human
urine to an amount of 4-9 vols. per cent — according to Pfliiger of
13-14 vols. per cent. The partial pressure of the C02 in the
urine is somewhat higher than in the blood (according to
Strassburger it is equal to -^ of an atmosphere), and rises some-
what in fever (Ewald).
The amount of combined carbonic acid in human urine is
usually less than that present in the free state (2-5 vols. per cent
according to Planer, 0'1-0'7 vols. per cent, according to Pfliiger),
and does not increase in fever (Ewald). The carbonates and
bicarbonates are alimentary, or come from the lactic, malic,
tartaric, succinic, and other vegetable acids introduced with the
foods, which are readily oxidised by conversion into carbonates.
This is the reason why the urine of herbivora and vegetarians is so
rich in carbonates, which give it an alkaline reaction, and cause it
to become turbid shortly after emission. On filtering off the
deposit, it is found to consist of calcium carbonate and phosphates.
Among the inorganic bases contained in urine, special mention
must be made of ammonia. Only a trace can be detected in the
free state previous to the commencement of alkaline fermentation,
in which the urea is converted into ammonium carbonate. The
chief part of the ammonia is found in the form of ammonium
salts (phosphates, carbonates, etc.) to an average daily amount of
0'7 grm. (Neubauer). For the same person, Coranda found 0'64
grm. after an ordinary mixed diet, 0'87 grm. after a flesh diet,
0'64 grm. with a vegetable diet. The influence of alimentation
on the ammonia content of the urine is therefore striking.
Injection of ammonium salts increases the amount present in
410 PHYSIOLOGY CHAP.
the urine, with the exception of ammonium carbonate, which
is converted into urea by the liver (supra). Schmiedeberg's
theory of the origin of the ammonia of the urine seems to us the
most acceptable. He holds that the small amount of ammonium
salts in the urine represent the residue of the large quantity of
ammonium carbonate (and, as we should add, of ammonium
carbamate also) which are formed along the course of the aliment-
ary canal, and which have escaped conversion into urea by the
liver.
The content of ammonium salts in the urine increases under
all conditions which produce increase of the acids absorbed from
without, or formed within the body (acid intoxication). The same
factors which tend to form oxalic acid and lactic acid in the dog
simultaneously increase the ammonia of the urine (Eeale and Boeri).
The same occurs in acute poisoning by phosphorus (Miinzer). The
ammonia content rises in the urine in high and persistent fevers,
as almost invariably in diabetes (Hallervorden, Coranda, Schmiede-
berg), probably because in these cases there is increased develop-
ment of acids in the body.
XL It is evident from this review of the most important
constituents of normal urine, that the physiological office of the
kidneys is to eliminate from the body the chief part of the waste
products developed by the katabolic processes of the tissues,
whether these metabolites are derived from the substances intro-
duced in the food, or from those which constitute the materials
proper of the bioplasm. This elimination is a real purging of the
organism, indispensable to the normal exercise of its functions.
Should the greater part of the urinary katabolites, either from
abnormal conditions, or from profound degeneration of the kidneys,
be retained in the blood and accumulate in the tissues, grave
phenomena of auto-intoxication arise which shortly cause the
death of the animal.
According to Prevost and Dumas (1822), animals do not
survive the loss of the kidneys for more than 42 hours ; according
to Cl. Bernard (1847-59), dogs can survive 50-75 hours. After
10-12 hours they vomit the food previously ingested, and
subsequently become depressed, weak, and refuse food, their
respiratory "movements become dyspnoeic, and they utter cries.
These phenomena grow more pronounced, with a tendency to
coma, and at a given moment, without any perceptible external
cause, the animal is seized with epileptic convulsions, which get
worse and worse, till it dies. On experimenting with a dog that
had previously been operated on by gastric fistula, Bernard
observed that the secretion of gastric juice, a few hours after
nephrectomy, increased considerably in quantity and became
continuous even during abstinence ; that it contained ammonium
salts, and preserved its acidity and digestive powers ; lastly, that this
vii KATABOLIC CONSTITUENTS OF UKINE 411
flow of gastric (and intestinal) secretion containing ammonium
salts persisted so long as the animal; retained its normal vivacity,
and diminished progressively during the aggravation of the
phenomena of auto-intoxication, during which only was there
increase of urea in the blood. In short, toxic phenomena were
not developed so long as the gastro-intestinal surface functioned
as the vicarious excretory system in place of the kidneys, and
when this vicarious function ceased, auto-intoxication set in, and
soon led to the death of the animal.
In the advanced stages of Bright's disease also, when the
impermeability of the urinary passages has become marked, a
very complex syndrome of auto-intoxication phenomena makes its
appearance, which is known to pathologists as uraemia — a most
inappropriate term, since this state depends less on the retention
of urea than on the sum of the other mineral and organic sub-
stances normally present in the urine, which exert a far greater
toxic action on the tissues. This was first demonstrated by Gallois
in Bernard's laboratory (1859), who found that the injection of
strong doses of urea into the blood did not produce permanent
disorders, such as are observed in the diseases caused by the
so-called " uraemia."
That urea in and per se is not toxic to vertebrates can also be
deduced from the striking fact, first pointed out by von Schroder
(1890), that the blood of certain fishes (Selachia) normally contains
urea in a concentration of 2-6 per cent, which approximately
corresponds with that at which it is normally present in human
urine. According to Baglioni (1905, see Vol. I. p. 297), the high
content of urea in the blood of these fishes is not only innocuous,
but even essential, in order that the myocardium shall function
properly.
Another method of demonstrating that the urine, as a whole,
normally contains toxic substances, consists in its intravenous
injection into animals, on which (when the quantity injected
reaches a certain maximum that increases with the body- weight)
toxic phenomena set in that are rapidly fatal. Feltz and Hitter
(1881) first performed this experiment successfully on rabbits, and
Bocci, at Moleschott's suggestion, shortly afterwards on frogs.
But the credit of establishing the importance of this method of
determining the toxicity of natural urine and its principal com-
ponents, is undoubtedly due to Bouchard (1887). He always
employed rabbits, by injecting the fresh urine either of a healthy or
of a sick man into the auricular vein, and then observed the toxic
phenomena, which varied with the varying dose of urine injected.
He gave the name urotoxia to the amount of toxic constituents
necessary for the lethal dose per kilo, of the animals experimented
on, and urotoxic coefficient to the amount of urotoxias eliminated
with the urine in 24 hours per kilo, body-weight.
412 PHYSIOLOGY
CHAP.
According to the average of Bouchard's results, the urotoxic
coefficient of man under normal conditions is equal to 0464, and
varies within narrow limits. In pathological conditions it rarely
exceeds 2, and rarely falls below 010.
The following was Bouchard's method of determining the urotoxic
coefficient of the urine : say that in a healthy man of 60 kilos, body-weight
1200 c.c. urine are excreted in the 24 hours. If 50 c.c. of this urine per kilo.
of the animal (rabbit) kill it, i.e. contain 1 urotoxia, then the 1200 c.c. urine
must contain 24 urotoxias. In effect, 50 : 1 : : 1200 : x, therefore
1200 ,
x = -5<r = 24-
If 60 kilos, of man produce 24 urotoxias per diem, 1 kilo, must produce
24
^. —0'4 urotoxias ;
0'4 is therefore the normal urotoxic coefficient.
On the hypothesis that susceptibility to urinary poisons is the same for
man as for rabbit, the amount of urine necessaiy to kill the man by whom
it has been excreted can be calculated. We have therefore the following
proportion : 24 : 1200 : : 60 : x, whence it results that
i.e. 3 litres of urine will kill a man of 60 kilos, body-weight who daily
excretes 24 urotoxias, viz. the urine passed in two days and eight hours.
The toxicity of normal urine is affected by cerebral activity,
muscular activity, sleep, nutrition, etc. The variations involve not
only the amount but also the nature of the urinary toxins. The
urine of sleep, although denser and richer in solid matters, is
nearly always, given the same volume and time of secretion, less
toxic than the urine of waking. During sleep, according to
Bouchard, man elaborates 2-4 times less poison than during the
corresponding period of cerebral activity. Further, the urine of
sleep produces convulsions, while that of waking is narcotic. The
body must, therefore, when awake manufacture substances which,
on their accumulation, induce sleep ; during sleep, on the contrary,
it accumulates such as discharge muscular twitches and provoke
awakening. On mixing the urine of sleep with that of waking,
the result is not average toxicity, but a toxicity lower than that
of the less toxic urine.
Muscular work, far from augmenting the toxicity of urine,
diminishes it by one -third, and this diminution persists for
several hours after the muscular activity ceases. According to
Bouchard these facts support the conjecture that the toxicity of
the urine depends not on its mineral constituents, which certainly
do not diminish with movement, but rather on the incompletely
oxidised organic substances, the toxicity of which diminishes in
proportion as they become oxidised.
vii KATABOLIC CONSTITUENTS OF UEINE 413
Bouchard's results are important to the exact determination of
the urinary constituents on which the various toxic phenomena
depend, and may be shortly summed up : —
Urea, although present in large quantities in the urine, is
certainly not the chief poison. Injection of urea into the veins
produces toxic effects only when it is present in such an amount
and concentration that the osmotic pressure of the blood is
seriously altered (6 '31 grms. urea per kilo, of the animal). In
moderate doses urea has a diuretic action, so that, far from acting
as a poison, it protects the body from auto-intoxication by acceler-
ating the expulsion of endogenous poisons.
• Nor can uric acid be regarded as a poison, since as much as
30 cgrms. per kilo, body weight -can be injected without effect.
Moreover, we know that man only forms 8 mgrins. uric acid per
kilo, in the 24 hours.
Although elaborated by the muscles in large quantities, the
innocuous character of creatine and creatinine has frequently been
demonstrated (Eanke, Schiffer).
An alcoholic extract of the dry residue of urine certainly contains
toxic substances, seeing that intravenous injection of an alcoholic
solution induces drowsiness, coma, diuresis, salivation. At present
we are quite ignorant as to what constituent or compounds the
narcotic and scialagogic action depends on : all we can say is that
the diuretic action is due to urea.
The urinary constituents which are insoluble in alcohol, on the
contrary, produce the opposite effects of convulsion, hypothermia,
myosis, without any symptoms of coma, salivation, or diuresis. It
is possible that these effects are due to the mineral substances.
Potassium salts, in fact, cause death with convulsive phenomena,
when injected to an amount of 0'5 grms. per kilo. Ammonium
salts also produce the same effect, but they are only present in
small quantities in the urine. It seems, however, as if we must
assume that there is in addition to these mineral poisons a substance
producing convulsions, which is represented by an organic con-
stituent insoluble in alcohol, seeing that night-urine produces
convulsive effects, which is not the case with the urine of waking,
— even after muscular fatigue, when more mineral salts are
present.
All the toxic effects obtained by intravenous injection of urine
into rabbits — coma, convulsions, myosis, salivation, hypothermia
— are also exhibited in the last stage of Bright's disease, and in
the anuria of Asiatic cholera. The sole difference observed in
these spontaneous diseases as compared with the effect of experi-
mental injection of urine into the blood consists in the fact that
in the latter there is an abundant flow of urine promoted by the
urea, which, as we have seen, has a diuretic action that proportion-
ately alleviates the effects of the intoxication.
414 PHYSIOLOGY CHAP.
Our knowledge of the toxicity of urine has been considerably
advanced by .the work of Colasanti and his pupils (1895-96, 1899).
He experimented on dogs instead of rabbits, finding them more
resistant to the urinary poisons. Indeed, the mean urotoxic
coefficient for normal dogs is, according to Colasanti, O182, a
much lower figure than that determined by Bouchard for rabbits
( = 0'465), showing that in dogs the resistance to these poisons is
2| times as great as that of rabbits.
On comparing the protective function of the kidneys with that
of the liver, Colasanti saw that when the toxicity of the bile is
maximal, that of the urine is minimal, and -vice versa. The kidneys
and liver can, therefore, act vicariously as purgative organs, when
elimination of the endogenous poisons is inadequately performed
by the one or the other system.
While studying the toxicity of the urine in diseases of the
liver in which the functions of this viscus are more or less altered,
Colasanti constantly observed urinary hypertoxicity, in ratio with
the degree of hepatic insufficiency. This increase of toxicity in
the urine is not in ratio with the amount of nitrogenous products
contained in it, which may increase or diminish according to the
different lesions of the hepatic parenchyma. It is therefore possible
from the increased toxicity of the urine to judge of the gravity of
the hepatic lesion, while its diminution may be a sign of recovery
of the hepatic functions.
The experimental proof of the relations between the hepatic
and renal functions is seen in the fact that after gradual
occlusion of the portal vein the urine of the animals operated on
becomes hyper toxic like that of liver-patients, since in this case
the whole of the toxic substances otherwise eliminated by the bile
find no outlet other than the kidneys. The same fact also shows
that part of the biliary or urinary poisons are formed in the
intestine, whence they are absorbed and carried to the circulation
by the portal roots, and on reaching the liver are once more turned
out into the intestine with the bile. Colasauti, in fact, showed that
the bile secreted after occlusion of the portal system is so much
less toxic in proportion as the toxicity of the urine becomes greater,
although the chemical composition of the secretion may differ
little from the normal.
The increase in the molecular composition of the blood observed
in uraemia, depends not so much on the mineral constituents
(bases, acids, salts) as on the organic compounds, which result
from tissue metabolism. As demonstrated by Viola and by
Bickel, the blood of nephrectomised or of uraemic patients does
not show any change in electrical conductivity. That the cause
of the uraemic phenomena lies in a specific toxic action of these
organic metabolites when retained in the body, and not, as Linde-
mann (1899) concluded, in the increased osmotic pressure of the
vii KATABOLIC CONSTITUENTS OF UEINE 415
blood, was demonstrated by Bickel (1901-3). By injecting
indifferent substances into the blood, he succeeded in raising its
molecular concentration to a much higher degree than is the case
in uraemia, without producing any of the symptoms exhibited by
hraemics.
F. Marino-Zuco and E. Onorato (1904-5) have recently found
a characteristic poison in urine to which they have given the name
of biotoxin, because it is found not only in urine, but in all
the tissues and fluids of the human and animal body. They
extracted it from urine by concentrating 50 litres in a special
apparatus, at a temperature of 38° C., under aseptic conditions,
till a fluid of syrupy consistency was obtained. From this, after
repeated precipitation with alcohol and washing of the precipitate,
they obtained the pure toxin in the form of a light, white,
amorphous powder, devoid of odour, insoluble in alcohol, and giving
no protein reaction.
This biotoxin is constantly present in the urine of man and
the higher vertebrates, both herbivora and carnivora, to an amount
of 0'3-0'5 per litre. It can, moreover, constantly be detected in
the kidneys and the blood ; and must therefore be a product of
metabolism, removed from the blood by the kidneys, and then
excreted. It has not yet been determined whether this elimina-
tion takes place solely in the kidneys, or whether other organs
share in it. In whatever way biotoxin is isolated it invariably
exhibits the same properties. Since on injection into the blood of
animals it induces morbid phenomena similar to those of uraemia,
while, on the other hand, there is less of it in nephritic than in
normal urine, Marino-Zuco and Onorato conjecture that the
accumulation of this poison in the blood, owing to functional
insufficiency of the kidneys, plays a considerable part in the genesis
of uraemia.
BIBLIOGRAPHY
The most important publications on the Constituents of Urine and their Origin
can be found in recent Text-books of Chemical Physiology and Monographs on
Urine, among which are : —
NEUBATTER and VOGEL. Anleitung zur qualitativen und quantitativen Analyse
des Harns. 10th ed., enlarged and brought up to date by Dr. H. Huppert.
Wiesbaden, 1898.
SALKOWSKI and LEUBE. Trattato dell' urina ad uso degli studenti e dei medici.
Italian translation. Naples, 1886.
REALS and BOERI. Manuale di chimica clinica. Analisi delle urine e ricambio
materiale. Naples, 1894.
L. ZOJA. Conferenze cliniche italiane dirette dal De-Giovanni, vol. i., 1897.
(This monograph contains a full, bibliography as regards the genesis of urinary
pigments. )
F. HOPPE-SEYLER and H. THIERFELDER. Handbuch der physiol. und patholog.
chemischen Analyse. Berlin, 1903.
A. HEFFTER. Ergebn. d. Physiol. i. Part I., 1902.
M. JACOBY. Ergebn. d. Physiol. i. Part L, 1902.
416 PHYSIOLOGY CHAP.
H. WIENER. Ergebn. d. Physiol. i. Part I., 1902.
AUERBACH and FRIEDENTHAL. Arch. f. (Anat. u.) Physiol., 1903.
R. HOBER. Beitr. z. chem. Physiol., 1904.
M. MAITHES. Arch. f. experim. Pathol. u. Pharmak. xlix.-li., 1903, 1904.
Toxicity of Urine : —
BOUCHARD. Lemons sur les auto-intoxications dans les maladies. Paris, 1897.
COLASANTI. Ricerche eseguite nell' Istituto di Farmacologia speriraentale, vols.
ii., iii., iv., Rome, 1895-96, 1899.
F. MARINO-ZUCO and R. ONORATO. Archivio di Fisiologia, vols. i. and ii., 1903-4.
Recent English Literature : —
W. J. SMITH JEROME. Further Proofs of the Origin of Uric Acid from Nuclein-
Compounds and Derivatives. Journ. of Physiol., 1899-1900, xxv. 98.
L. B. MENDEL and E. W. BROWN. Observations on the Nitrogenous Metabolism
of the Cat, especially on the Excretion of Uric Acid and Allantoin. Amer.
Journ. of Physiol., 1900, iii. 261.
W. J. GIES. A Note on the Excretion of Kynurenic Acid. Amer. Journ. of
Physiol., 1901, v. 191.
L. B. MENDEL and E. C. SCHNEIDER. On the Excretion of Kynurenic Acid (II.
paper). Amer. Journ. of Physiol., 1901, v. 427.
R. E. SWAIN. The Formation of Allantoin from Uric Acid in the Animal Body.
Amer. Journ. of Physiol., 1902, vi. 38.
0. FOLIN and P. A. SHAFFER. On Phosphate Metabolism. Journ. of Physio].,
1902, vii. 155.
0. FOLIN. The Acidity of Urine. Amer. Journ. of Physiol., 1903, ix. 265.
G. H. A. CLOWES. The Relationship between the Freezing Point, Depression and
Specific Gravity of Urine, under Varying Conditions of Metabolism, and its
Clinical Value in the Estimation of Sugar and Albumin. Amer. Journ. of
Physiol., 1903, ix. 319.
G. C. GARRATT. Further Observations on the Sequence of Changes produced in
the Urine as a Result of Exercise. Journ. of Physiol., 1903, xxix. 9.
A. E. GARROD. Some Further Observations on the Reactions of Urochrome with
Acetaldehyde. Journ. of Physiol., 1903, xxix. 335.
P. B. HAWK and J. S. CHAMBERLAIN. A Study of the Variations in the Course
of the Nitrogen, Sulphate, and Phosphate Excretion, as observed in Short
Periods following a Small Increase in the Proteid Ingested. Amer. Journ. of
Physiol., 1904, x. 269.
R. E. SWAIN. Some Notable Constituents of the Urine of the Coyote. Amer.
Journ. of Physiol., 1905, xiii. 30.
0. FOLIN. Approximately Complete Analyses of Thirty " Normal " Urines. Amer.
Journ. of Physiol., 1905, xiii. 45.
E. W. ROCKWOOD. The Elimination of Endogenous Uric Acid. Amer. Journ. of
Physiol., 1905, xii. 38.
W. KOCH. Relation of Kreatinin Excretion to Variations in Diet. Amer. Jour
of Physiol., 1905-6, xv. 15.
0. E. CLOSSON. The Elimination of Creatinin. Amer. Journ. of Physiol., 1906
xvi. 252.
J. J. R. MACLEOD and H. D. HASKINS. Contributions to our Knowledge of the
Chemistry of Carbamates. Journ. of Biol. Chem., 1905-6, i. 319.
A. E. GARROD and T. SHIRLEY HELE. The Uniformity of the Homogentisic Acid
Excretions in Alkaptonuria. Journ. of Physiol., 1905-6, xxxiii. 198.
A. E. GARROD and W. H. HURTLEY. On the Estimation of Homogentisic Acid it
Urine by the Method of Wolkow and Baumann. Journ. of Physiol., 1905-6,
xxxiii. 206.
A. E. GARROD and W. H. HURTLEY. Concerning Cystinuria. Journ. of Physiol.,
1906, xxxiv. 217.
F. G. BENEDICT and A. R. DIEFENDORF. The Analysis of Urine in a Starvir
Woman. Amer. Journ. of Physiol., 1907, xviii. 362.
F. G. BENEDICT and V. C. MYERS. The Determination of Creatine and Creatinine
Amer. Journ. of Physiol., 1907, xviii. 397.
vii KATABOLIC CONSTITUENTS OF UEINE 417
F. G. BENEDICT and V. C. MYERS. The Elimination of Creatiue. Amer. Journ.
of Physiol. , 1907, xviii. 406.
E. W. ROCKWOOD and C. VAN EPPS. The Influence of some Medicinal Agents on
the Elimination of Uric Acid and Creatinin. Amer. Journ. of Physiol., 1907,
xix. 92.
E. OSTERBERG and C. G. L. WOLF. Day and Night Urines. Journ. of Biol. Chem.,
1907, iv. 165.
E. P. CATHCART and J. B. LEATHES. On the Relation between the Output of
Uric Acid and the Rate of Heat Production in the Body. Proc. Roy. Soc.
of London, 1907, Ixxix. B. 541.
J. F. GASKELL. A Method of Quantitative Estimation of Cystin in Urine. Journ.
of Physiol., 1907-8, xxxvi. 142.
A. E. GARROD and W. H. HURTLEY. On the Supposed Occurrence of Uroleucic
Acid in the Urine in some Cases of Alkaptonuria. Journ. of Physiol., 1907-8,
xxxvi. 136.
C. A. HERTER. The Relation of Nitrifying Bacteria to the Urorosein Reaction of
Nencki and Sieber. Journ. of Biol. Chem., 1908, iv. 235.
C. A. HERTER. On Indolacetic Acid as the Chromogen of the "Urorosein" of the
Urine. Journ. of Biol. Chem., 1908, iv. 253.
E. MELLANBY. Creatin and Creatinin. Journ. of Physiol., 1908, xxxvi. 447.
P. SHAFFER. The Excretion of Kreatinin and Kreatin in Health and Disease.
Amer. Journ. of Physiol., 1908-9, xxiii. 1.
P. J. HANZLIK and P. B. HAWK. The Uric Acid Excretion of Normal Men.
Journ. of Biol. Chem., 1908-9, v. 355.
P. A. LEVENE and L. LEVENE. Factors regulating the Creatinin Output in
Man. Amer. Journ. of Physiol., 1909, xxiv. 45.
E. Q. KENNAWAY. The Effects of Muscular Work upon the Excretion of Endo-
genous Purines. Journ. of Physiol., 1909, xxxviii. 1.
T. S. HELE. Metabolism in Cystinuria. Journ. of Physiol., 1909-10, xxxix. 52.
R. H. A. PLIMMER, M. DICK, and C. C. LIEB. A Metabolism Experiment with
Special Reference to the Origin of Uric Acid. Journ. of Physiol., 1909-10,
xxxix. 98.
E. L. KENNAWAY. On the Estimation of Purine Bases in Urine. Journ. of
Physiol., 1909-10, xxxix. 296.
S. R. BENEDICT. The Estimation of Total Sulphur in Urine. Journ. of Biol.
Chem., 1909, vi. 363.
D. NOEL PATON. Creatine Excretion in the Bird and its Significance. Journ. of
Physiol., 1909-10, xxxix. 485.
H. G. WELLS. The Purine Metabolism of the Monkey. Journ. of Biol. Chem.,
1909-10, vii. 171.
L. B. MENDEL and H. D. DAKIN. The Optical Inactivity of Allantoin. Journ. of
Biol. Chem., 1909-10, vii. 153.
L. B. MENDEL and J. S. KLEINER. The Fate of Saccharose after Parental Intro-
duction in Animals. Amer. Journ. of Physiol., 1910, xxvi. 396.
H. D. DAKIN. The Fate of Inactive Tyrosine in the Animal Body together with
some Observations, etc. Journ. of Biol. Chem., 1910-11, viii. 57.
C. C. ERDMANN. On the Alleged Occurrence of Trimethylamine in Urine. Journ.
of Biol. Chem., 1910-11, viii. 57.
L. B. MENDEL and J. F. LYMAN. The Metabolism of some Purine Compounds in
the Rabbit, Dog, Pig, and Man. Journ. of Physiol., 1910-11, viii. 115.
P. A. LEVENE and E. MEDIGRECEANU. On Nuclein Metabolism in the Dog.
Amer. Journ. of Physiol., 1910-11, xxvii. 438.
A. J. WAKEMAN and H. D. DAKIN. Note iipon Relationship between Urea and
Ammonium Salts. Journ. of Biol. Chem., 1911, ix. 329.
VOL. II 2 E
CHAPTER VIII
THE EXCBETION OF URINE
CONTENTS. — 1. Structure of the kidneys. 2. Mechanism of urinary secretion.
Vitalist theory of Bowman ; mechanical theory of Ludwig. 3. Modification of
urinary secretion with variations of normal conditions of circulation in kidneys ;
conclusions as to functions of glomeruli. 4. Effect on renal secretion of alterations
caused in the blood by diuretics ; criticisms of mechanical theory. 5. Experimental
data in favour of vitalist theory ; criticisms. 6. Innervation of kidneys. 7. Modi-
fications of epithelial cells of renal tubules during secretory activity and functional
rest. 8. Function of ureters. 9. Mechanism of retention of iirine. 10. Mechanism
of micturition. 11. Innervation of bladder. Bibliography.
THE Kidneys are the organs that secrete urine ; the Ureters are
the canals that conduct the urine to the bladder, from which it is
periodically expelled through the urethra. These organs as a
whole form the Uropoietic System, the functions of which will be
considered in the present chapter.
I. In order to form any idea of the mechanism by which the
chemical constituents of the urine are separated from the blood, it
is necessary to start with the structure of the kidney. In no other
glandular organ do the structural peculiarities, the relations
between circulatory system and excretory ducts, correspond as
strictly as in the kidneys with the specific character of the
functions. For this reason physiological theories as to the
mechanism of urinary secretion first assumed a scientific character
after the discovery of the highly characteristic structure of the
kidneys, by which they are differentiated from all other glands.
The following were the most fundamental discoveries in regard
to the morphology of the kidneys : Bellini (1661) first described
the uriniferous tubules to which the kidney owes its character of a
tubular gland. Malpighi (1669) first described the corpuscles
that bear his name, and succeeded in injecting them through the
arteries; he regarded them as small glands, for which Bellini's
ducts form the excretory system. Huschke (1828) first pointed
out that in birds and batrachia the uriniferous tubules end in the
form of spherical dilatations. Johannes Mtiller (1830) shortly
after discovered these dilatations in the uriniferous tubules of all
vertebrates ; but he did not detect their connection with the blood-
418
CHAP. VIII
THE EXCRETION OF UEINE
419
vessels, and relation to the Malpighian corpuscles, which he took
to be simple vascular tufts, distinct from the dilatations of the
ducts. Bowman (1842) first recognised the fundamental fact
that the vascular glomeruli are enclosed in the spherical dilatations
which he designated capsules — in other words, that the Malpighian
corpuscles are terminal expansions of the uriniferous tubules,
embracing a vascular glomerulus (Fig. 108).
The Malpighian corpuscles and their relation to the afferent
and efferent blood-vessels are plainly seen on injecting the vessels,
Fio. 108.— (Left.) Diagram showing relation of uriniferous tubules to blood-vessels. (After Bow-
man.) a, one of the interlobular arteries ; a', afferent artery passing into glomerulus ; c,
capsule of glomerulus ; t, convoluted tube ; e' e', efferent vessels which subdivide in plexus p,
surrounding the tube, and finally terminate in interlobular vein, c.
PIG. 109.— (Right.) Plan of longitudinal section through pelvis and substance of right kidney.
One-half the natural size, a, cortical substance ; 6, b, broad part of two pyramids of Malpighi ;
c, c, the divisions of the pelvis named calices of infundibula, laid open ; c7, one of these, unopened ;
d, d, summit of pyramids or papillae projecting into calices ; e, e, section of narrow part of two
pyramids near the calices ; p, pelvis or enlarged portion of ureter within the kidney ; u, ureter ;
s, sinus ; h, hilum.
while non-injected preparations show the connection of the
capsules with the ducts. All subsequent work has merely
extended and completed the discovery of Bowman, who confirmed
the physiological concept formed by Malpighi from the corpuscles,
and so long contested by Euysch and his adherents. Bowman,
however, made one fundamental modification in Malpighi's theory,
inasmuch as he held that the renal corpuscles excreted water,
and the uriniferous tubules the characteristic constituents of
urine. Malpighi and Johannes Miiller were the precursors,
Bowman was the creator, of the physiological theory of renal
secretion.
We must briefly consider the structure of the kidney. It is
surrounded by a fibrous coat known as the capsule, which can
420
PHYSIOLOGY
CHAP.
easily be detached, since it is only connected with the substance of
the gland by minute processes of connective tissue and small
vessels. If split up longitudinally, it presents the anatomical
features shown by
Fig. 109. The cor-
tical substance is
reddish - brown, the
medullary pale and
fibrous. In man the
latter consists of
about ten Malpig-
hian pyramids, the
; points of which con-
verge towards the
pelvis which receives
the secretion. An
intermediate layer
can be distinguished
from the cortical and
medullary substance,
exhibiting character-
istics common to both
(Henle).
Each Malpighian
pyramid consists of a
large bundle of urini-
ferous tubules, which
are straight in the
medullary part
(tubuli recti of
Bellini), and con-
voluted in the corti-
cal part (tuhuli con-
torti of Ferrein). The
straight tubules of
the pyramids are
prolonged into the
cortical substance
almost to the surface
FIG. 110.— Diagram of course of two uriniferous tubules. (Klein.) of the kidney, where
.4, cortex; B, boundary zone; C, papillary zone of medulla; .1 f ,. -mprliil
a, a', superficial and deep layers of cortex, free from glomeruli.
lary rays, visible to
the unaided eye, from which the convoluted tubules deflect to
form the labyrinth of the cortex.
Fig. 110 gives a diagram of the course of the uriniferous
tubules from their origin in the Malpighian corpuscles (Bowman's
capsules enclosing the vascular glomerulus) to their opening upon
VIII
THE EXCRETION OF URINE
421
substance of human kidney. (Bohm and v. Davidoff.)
a, basement membrane of outer layer of capsule ; g,
epithelium of capsule ; eg, glomerular epithelium ;
vs, section of blood-vessel; 1, 3, 3, h, 5, lobules of
glomerulus ; co, neck at commencement of uriniferous
tubule, lined transitional epithelium ; ep, epithelium
of convoluted tubule.
the papillae into the calicos of the renal sinus. Each tubular
orifice with its multiple ramifications represents a pyramid of
Ferrein — -the morphologi-
cal unit from which the
pyramids of Malpighi arise.
For physiologists the
chief interest attaches to
the structure of the differ-
ent parts of the uriniferous J.../
tubules, and the epithelial
cells with which these are
lined, in the hope of dis-
tinguishing the secretory
portion of the tubules from
such parts as simply con-
duct the urine.
Bowman's capsule,
which surrounds the
glOmerUlUS as tne SerOUS pIO m_ —structure of a Bowman^ capsule from cortical
coat surrounds the viscera,
consists of an external
layer, formed of a struc-
tureless basement mem-
brane, lined with flattened
epithelium, and an internal or visceral layer which lines the
glomeruli, and dips down
between the loops and lobules.
In the adult its cells do
not form a definite and con-
tinuous layer (Fig. 111). In
the foetus, on the contrary
(when the vascular loops of
the glomerulus are still un-
developed), the stratum of
cells that completely sur-
rounds the glomerulus is
much more distinct (Fig. 112).
There is an intracapsular
space between the two layers,
which almost disappears when
the vessels of the glomerulus
are injected ; and which com-
municates freely with the
neck of a convoluted tubule,
where transitional forms
between the flattened epithelium of the outer layer of the capsule
and the cubical cells that line the tubules, may be detected.
Fir,. 112.— Section of cortical substance of kidney ;
human foetus. Highly magnified. (Klein.) a,
glomerulus with blood-vessels not fully developed ;
b, connective tissue between the blood-vessels ; c,
epithelium covering it continuous with d', flattened
epithelium lining Bowman's capsule ; /, /, con-
voluted tubes.
422
PHYSIOLOGY
CHAP.
The convoluted tubules, too, consist of a structureless basement
membrane covered with cubical epithelium, the turbid protoplasm
of which is thickly set with granules in such regular lines that
(more particularly in the outer basal half) they present an effect of
striation. At the inner edge facing the lumen, there is, according
to the observations of Former (confirmed by many workers,
particularly by Sauer, 1895, in Germany, and by E. and A. Monti,
1900, in Italy), a sort of finely striated border, which looks
like the bristles of a brush, and is therefore known as the orlo a
spazzola ("brush border," Fig. 113). Later on we shall see what
changes this characteristic epi-
thelium undergoes, according to
the functional state of the kidney.
The epithelium of Heule's
loops differs in the narrow de-
scending and the wider ascending
limb. In the former the basement
membrane is covered by a flattened
epithelium, the nuclei being pro-
minent towards the lumen. As
shown in Fig. 114, three cells,
more often two, still more often
one flattened cell, are enough to
line the entire lumen of the canal.
The alternating position of these
cells gives a spiral character to
^^^ the tubule. The lumen does not
exceed 9-15 /*, i.e. it is approxi-
FIG. us. —section of convoluted tubule of mately equal to that of the blood
waking marmot, during functional activity "M
of renal epithelia. (R and A. Monti.) CapUiariCS.
In the ascending limb of
Henle's loops the epithelium is cubical, and the cells project so as*
to restrict the lumen, and make it narrower than in the descending
limb, although as a whole the diameter of the tubules exceeds
25 p.
In the second convoluted tubules, which unite Henle's looj
with the ducts of Bellini, the same characteristic cells recur as in
the first convoluted tubules. The cells, however, are smaller,
while the diameter of the tubule is about the same (36-46 //).
The epithelium of the straight collecting tubes has clear eel
with no appearance of striation. They are cubical at first, and
gradually become columnar as the size of the lumen increases.
The nucleus is always round and sharply defined.
In the large collecting tubes or papillary ducts the basement
membrane is strengthened by connective tissue. The diameter at
the orifices upon the papillae may be 1 mm.
The arrangement of Hood-vessels in the kidneys is no less
vi n THE EXCRETION OF URINE 423
characteristic than that of the uriniferous tubules. The renal
artery given off from the aorta enters the kidney at the hilum.
It is exceptionally large in proportion to the size of the organ.
The renal vein, which leaves by the hilum, and opens directly into
the inferior vena cava, is still larger. Both artery and vein give
off a number of branches which penetrate into the substance of
the organ between the papillae (arteriae and venae interlobulares),
and form arches at the junction of the medullary and cortical
substance (arterial and venous arches, the latter anastomosing
~
<;«^y VrS w; r •©
£&X: &/- ^ f \^ '> X^9 >-a^
FIG. 114.— Section through fragment of human kidney at the level of Henle's intermediate zone
between the cortex and medulla. (Szymonowicz.) Tc, collecting tubules of Bellini ; Hd,
descending limb of Henle's loops ; Ha, ascending limb of Hente's loops ; Fs, blood-vessels ; c,
iritertubular connective tissue.
freely among themselves). The arches give off peripheral branches
(arteriae and venae interlobulares) which pursue a nearly straight
course towards the surface of the organ, and give off short and
usually curved branches at intervals (Fig. 115). The venous
branches form a capillary network, and the arterial form the vasa
afferentia, which penetrate into the capsule or dilated extremity
of the uriniferous tubules. Within the capsule the afferent vessel
breaks up into a much convoluted capillary mass, the vascular tuft
or glomerulus, which is usually divided into lobules anastomosing
among themselves. The glomerular capillaries unite into a single
efferent vessel which is always smaller than the afferent, and
which leaves the glomerulus close to the point at which the artery
enters (Fig. 116). This efferent vessel breaks up after the manner
424
PHYSIOLOGY
CHAP.
of an artery into smaller branches, which end in a dense capillary
network, and ramify over the walls of the uriniferous tubules, —
their meshes being polygonal in the
cortex, and elongated in the medulla.
While the blood which supplies the
cortex of the kidney traverses the inter-
lobular arteries to the glomeruli, and is
thence conveyed by the capillary net-
work of the interlobular veins (as well
as the venae stellatae), the blood supply
for the medulla passes through the
arteriae rectae, which are given off from
the arterial arches close to the inter-
lobular arteries, and then descend to-
wards the hiluin, divide into minute
branches which form brushes or bundles,
and end in the long-meshed capillary
network of the medulla, after which
they are collected into the venae rectae
which are intermixed with the arteries
of the same name. There is thus a
comparative independence between the
cortical and the medullary circulation,
although they unite in a common net
work of capillaries.
VfJ
FIG. 115.- (Left.) Diagram of distribution of blood-vessels in human kidney. (Ludwig.) ai,
interlobular arteries ; vi, vi, interlobular veins ; g, glomerulus ; vs, stellate vein ; or, n; --'
et venae rectae forming pencil-like bundles, ab, vb ; vp, venous plexus in the papillae.
FIG. 116.— (Right.) Malpighian glomerulus of injected human kidney. (Szymonowicz.) Fa,
afferent vessel enormously enlarged by passive dilatation owing to pressure of injected fluid;
Ve, efferent vessel, which is always much smaller than the afferent, but the difference in this
case is much exaggerated ; 1, 2, 3, k, vascular lobules of glomerulus.
The uriniferous tubules and blood-vessels of the kidney are
united by interstitial connective tissue, which is more abundant in
viii THE EXCRETION OF URINE 425
the neighbourhood of the papillae than in other parts of the
kidney substance. The spaces not filled by connective tissue are
lined in some places by epithelioid platelets, and form the lymph
channels which bring to the epithelial cells of the uriniferous
tubules both nutrient materials and the urinary constituents,
which, as we shall see, it is their office to expel.
The renal artery, at the point at which it enters the hilum of
the kidney, is surrounded by a plexus of nerve filaments (plexus
renalis), which consists partly of medullated fibres, varying con-
siderably in size, but principally of non-medullated fibres. The
nerves of the renal plexus come chiefly from the great solar plexus,
which contains fibres of the vagus, as well as of the greater and
lesser splanchnic nerves. Numerous small ganglia are also present
in the renal plexus.
The peripheral relations of the nerve fibres of the kidneys
with the branches of the small arteries, and with Bowman's
capsule and the convoluted tubules, were worked out in 1893 by
Berkley. We shall discuss the importance of this discovery later.
Besides the vasomotor and the secretory fibres, there are
undoubtedly sensory fibres to the kidney, seeing that in certain
morbid conditions the kidneys can be the seat of acute pain.
II. The Secretion of Urine is constant, but it fluctuates con-
siderably with different circumstances, even under normal condi-
tions. On introducing cannulae into both ureters of an animal
(or of man by means of the urethral catheter, as clinically
employed) it can be seen that, independent of irregularity and
asymmetry of excretion, due to the peristalsis of the ureters,
secretion is never parallel in both kidneys, but is greater now in
the right, now in the left. Apparently there is a kind of alterna-
tion of secretory activity and of blood supply in the two kidneys
(Ludwig). This shows that the secretion depends not only upon
general central conditions, but also upon local peripheral condi-
tions which vary in each kidney at different times.
Although bilateral nephrectorny is fatal in a short time by
causing uraemic intoxication (supra], the excision of one kidney
alone is compatible with life under normal conditions, not merely
in animals but also in man, on whom it has repeatedly been
carried out as a surgical operation. This fact shows that removal of
one kidney does not diminish the total secretion, and that the
kidney which is left may supplement and compensate the lost
function of the other, by increased secretory activity.
So long as the urinary secretion is going on, i.e. as long as
urine continues to trickle from the cannula fixed to the ureter,
the blood that leaves the kidney by the efferent vein is not dark
like the venous blood returned from the muscles, but bright red,
like arterial blood (Cl. Bernard). This shows that the velocity of
circulation in the kidney is much greater than in the other organs,
426 PHYSIOLOGY CHAP.
so that the arterial blood from the renal artery, although it meets
with an enormous resistance in the glomeruli and still more in the
capillary network, does not remain long enough in the kidneys to
acquire the characteristics of venous blood.
This peculiar rapidity of circulation in the renal vessels
evidently depends on the great difference in pressure between the
blood of the artery and that of the efferent vein ; the former comes
from the aorta, where pressure is maximal, the latter opens direct
into the vena cava, where pressure is almost nil, owing to the
proximity of the thorax. But for a complete explanation of the
phenomenon, it must also be remembered that the renal artery is
exceptionally large in comparison with the size of the kidney, so
that the arterial blood circulates in the kidneys not only with
greater velocity, but also in a larger amount tthan in other organs.
Even, therefore, on the assumption that the renal tissue consumes
no less oxygen during its secretory activity than the other
secretory organs (as proved by the fact that there is a marked
development of heat in the kidneys, since the temperature of the
urine, according to Grijns, is 0*4° C. higher than that of the blood
which flows into it) we can see why the blood that has passed
through it retains all the characters of arterial blood.
In regard to the process of Urinary Secretion there are two
rival theories, the physiological or vitalist theory of Bowman
(1842), and the mechanical theory of Ludwig (1844). Since all the
existing data derived from innumerable experiments in this much-
contested field relate either to the one or to the other of these, it
will be well to summarise them briefly.
Bowman's theory was founded upon considerations derived
from the morphological structure of the kidney. As we have seen,
he discovered in the Malpighian corpuscles the intimate relation
between the blood circulating in the kidneys and the commence-
ment of the uriniferous tubules, and therefore held them to be the
apparatus by which the salts and water of the urine are excreted.
On the other hand, the secretion of the specific constituents of
urine (urea, uric acid, etc.) must be effected by the physiological
activity of the epithelial cells that line the uriniferous tubules.
As it passes through these tubes, the water which is expelled by
the glomeruli must dissolve and carry off the urinary constituents
actively withdrawn from the lymph by the epithelial cells, and
secreted at their free surface.
To Bowman, therefore, the uriniferous tubules were the true
secretory apparatus, similar to that of any other gland, while the
glomeruli were a contrivance peculiar to the kidney, which
principally served to regulate the water content of the blood and
to facilitate the expulsion of the secretion from the tubules.
Ludwig, on the other hand, considered the glomeruli to be an
apparatus for filtration, through which not merely water, but also
viii THE EXCKETION OF UKINE 427
the whole of the crystalloid constituents of urine contained in the
blood plasma, were given off from the blood circulating through
them. Filtration is passively determined by the great difference
of pressure between the interior of the, glomerular capillaries and
the cavity of Bowman's capsule. The filtrate from the glomeruli
differs from that of the ordinary blood capillaries merely in con-
taining no protein, or traces only, because the walls of the
glomerular vessels are more resistant than those of the ordinary
capillaries, so long as they are under normal conditions. This
filtrate, then, has every characteristic of a very dilute urine.
During its passage through the uriniferous tubules it gradually
becomes concentrated by reabsorption of water into the lymph
that surrounds the tubules, which, having become poor in water
and rich in protein owing to the absorption of water in the
glomeruli, now takes up water by endosmosis. Thus, on Ludwig's
theory, the whole process of urinary secretion can be mechanically
explained as an effect of filtration and osmosis, without the inter-
vention of any specific secretory activity of the cells which
surround the glomeruli and line the tubules.
We must now review the experimental data of the subject,
using them as tests of the value of either theory, by which the
ground will be cleared for the construction of another intermediate
explanation, which may harmonise better with the physiological
facts as a whole.
III. The mechanism of urinary secretion can be experimentally
modified in two different ways : —
(a) Disturbance of the normal conditions of vascular circula-
tion in the kidneys, with various methods.
(&) Alteration of the normal constitution of the blood, by
various means.
The fact that the secretion of urine is intimately bound up
with the circulatory conditions in the kidneys has been established
by a series of convincing experiments. It is, however, necessary
to define exactly on what circulatory conditions increase of
secretion depends, and on what its decrease or total suspension.
Various experiments on animals show that the amount of
urine flowing from the ureters increases or decreases with rise or
fall of arterial pressure. Thus on bleeding an animal copiously
the flow of urine into the ureters diminishes in proportion with
the fall of aortic pressure ; on re-injecting the blood that has
been lost, the flow of urine is accelerated, as the aortic pressure
regains its initial value.
Goll (1854), in Ludwig's laboratory, obtained 8-9 grms. urine
from the ureters of a large dog in 30 min. before bleeding, 4'92
grms. after a loss of 530 grms. of blood, 7-66 grms. immediately
after transfusion of the blood that had been lost.
Stimulation of the cervical vagus, by which the beats of the
428 PHYSIOLOGY CHAP.
heart are retarded or suspended, causes a fall of aortic pressure
accompanied by a diminished now of urine, which becomes normal
again when the ordinary cardiac rhythm is re-established. From
the two ureters of a dog, Goll collected 9'15 gnus, urine every 30
minutes under normal conditions ; 10 grms. after division of the
vagi ; 2'36 grms. during the stimulation of one vagus ; 7'22 grms.
immediately after cessation of the stimulus.
When aortic pressure is raised by tying the large arteries, the
amount of urine eliminated increases proportionally. Thus in an
experiment in which Goll tied both carotids, both femorals, and
both cervical arteries, the aortic pressure rose from 127 to 142 min.
Hg, and the amount of urine secreted increased from 8*7 grms.
to 21 grms. every 30 minutes.
Transverse section of the cervical cord suspends the flowr of
urine, by lowering aortic pressure. This fact was first determined
by Cl. Bernard (1859), and was more closely studied by Ustimo-
witsch with Ludwig (1870), and by Griitzner with Heidenhain
(1875). According to the former the secretion is arrested when
the aortic pressure sinks to 40-50 mm., according to Griitzner when
it falls to a value of 30 mm.
When aortic pressure is constant, the urinary secretion can be
modified by increasing or diminishing the resistance which the
blood encounters in passing through the Malpighian glomeruli.
Thus Max Herrmann (1859), in Lud wig's laboratory, showed that
it was possible by moderate compression of the renal artery
retard the secretion of urine, while by occluding the vessels it can
be entirely suppressed. In exceptional cases, however, in certain
animals, the secretion of urine continues, though much reduced,
even after ligation of the renal arteries. This is explained by the
fact that in these animals capsular arteries exist which are
capable of supplementing the large artery that enters by the
hilum.
Division of the nerve filaments which accompany the rena
artery to the point at which it enters by the hilum produces
vasomotor paralysis of the kidney, so that it increases in volume
and secretes a larger amount of urine (Bernard, 1859 ; Eckhard,
1869). The polyuria commences after a brief secretory pause,
augments progressively, and reaches its maximum after 30-6(
minutes. The urine secreted after section of the nerves of the
renal plexus not infrequently contains albumin, and also haemo-
globin (Krimer and others); but this fact is not constant and
depends on the gross alterations in the circulatory conditions of
the kidney due to the effects of operation. In fact, when th(
principal nerve filaments are divided with great care, polyuria ie
produced without alburninuria or haemoglobinuria (Herrmann).
If, instead of section, the renal nerves are electrically stimulated,
a vaso-constriction results which diminishes or arrests the secretion.
viii THE EXCEETION OF UEINE 429
The same effect is obtained by stimulation of the splanchnic, and
of the medulla oblongata or spinal cord (Eckhard), also by arrest
of the respiratory movements which produces asphyxia (Griitzner).
This operation, as we know, causes a conspicuous rise, of aortic
pressure owing to diffused vaso-constrictor action ; but since the
branches of the renal artery also contract, the renal circulation is
diminished, not increased, consequently instead of a rise there is
a fall in urinary secretion. When, on the contrary, the splanchnic
and spinal cord are excited after division of the nerves of the renal
plexus on one side, there is marked acceleration of urinary secretion
on the side operated on, while in the other kidney it is entirely
arrested (Griitzner).
These experimental facts as a whole seem at first sight to lend
substantial support to Ludwig's theory, by which the renal
glomeruli are regarded as a mere filtering apparatus. In fact, when
blood pressure rises or falls in the renal artery (and therefore in
the glomeruli) the secretion of urine also must increase or decrease,
because the difference between the glomerular and the capsular
pressure, which mechanically causes the phenomenon of filtration,
becomes greater in the first case and less in the second. To this
it may be objected that under all the experimental conditions
above described in which pressure was altered in the renal artery,
the velocity of the renal circulation was altered' in the same
direction. Other experimental data tend to show that the renal
secretion depends not so much upon the pressure as upon the rate
at which the blood circulates in the kidneys. In fact, if a rise of
blood pressure be artificially produced in the kidneys together with
a delay or block in the current, there is no increase in the flow of
urine, but the exact opposite occurs, i.e. diminution or arrest of
the secretion.
It has long been known that compression or ligation of the
efferent veins will ipso facto produce a decrease or arrest of the
urinary secretion (B. H. Meyer, 1844; Frerichs, 1851; Ludwig,
1856).
According to Ludwig this fact does not contradict his filtration
theory, because the occlusion of the vas efferens produces such a
swelling of the interlobar and interlobular renal veins, that the
tubules which conduct the urine are compressed, and the flow of
urine from the papillae is impeded. This fact, however, might be
due to the arrest of the vascular circulation, which produces
asphyxia and alters the nutrition of the glomerular epithelium —
as thought by Heidenhain (1883). In fact, when the vein is
freed and the circulation re-established, albuminuria sets in for a
certain time. In any case Ludwig's interpretation is not applicable
to the fact that simple constriction of the renal veins without
interruption of the circulation suffices to reduce the flow of urine
to a minimum (Senator, Paneth). The same result can also be
430 PHYSIOLOGY CHAP.
obtained on making an artificial circulation through the vessels of
a kidney recently excised from the animal (I. Munk).
It is accordingly rate of circulation rather than pressure which
governs the phenomenon of renal secretion. On the velocity of
the blood-flow depends not only the amount of excretory material,
but also the provision of oxygen required by the secretory cells
for their task. In proof of this we have the fact that when the
integrity of the living cells of the capsular epithelium of the
glomerulus is damaged, their function ceases at once, either for a
time or permanently.
If, after a brief occlusion of the renal arteries, the renal circula-
tion is reinstated by opening the vessels, secretion is not resumed
at once, but after a certain lapse of time, which may vary from a
few minutes to three quarters of an hour. This phenomenon,
first observed by Max Herrmann in Ludwig's laboratory in 1859,
is not adequately explained by the theory which regards the
glomerulus as a passive filter, but is readily explained on the
assumption that the secreting epithelia of the glomerulus are
highly sensitive even to a temporary deprivation of oxygen, and
require a certain time to recover from the effects of asphyxia.
Overbeck's experiments (1863) confirm this hypothesis. He
observed that after occlusion of the renal artery, lasting only for
one and a half minutes, the secretion came back slowly after
forty-five minutes; that the first urine collected was scanty in
amount, and contained much protein ; that the quantity of urine
subsequently increased, while the protein content diminished;
that, lastly, the urine gradually regained its normal constitution.
Herrmann endeavoured to explain the arrest of the urinary secre-
tion on the hypothesis that the suspension of circulation produces
such an accumulation of blood corpuscles in the capillary network
of the kidney as to block the renal circulation ; but this hypothesis
was contradicted by Litten, who proved that even after prolonged
occlusion of the artery the renal circulation remained normally
pervious.
We hold the only acceptable interpretation to be that the
asphyxia of the living cells of the glomerulus alters them so as to
render them at first impermeable, and then at a second period,
after the circulation has been restored, abnormally permeable (even
to colloid substances). The fact that temporary albuminuria can
also be produced by suffocation, by strychnine poisoning, and
lastly by temporary obturation of the right heart (Overbeck),
agrees with this interpretation.
That velocity of the blood-flow rather than pressure is the
determining factor in the formation of urine is a fact of the
utmost importance to the theory of urinary secretion. Murri was
the first to put forward this idea in Italy, in his clinical lectures
on Haemoglobinuria a frigore, published 1879, as a rejoinder to
vni THE EXCEETION OF UEINE 431
Euneberg. Some months later Heidenhain attacked the same
problem iu Germany, and criticised the mechanical theory in a
communication to the medical section of the Breslau Gesellschaft
flir vaterlandische Kultur (December 1879).
But it must not be concluded on the strength of this fact that
Ludwig's theory, by which the Malpighian tufts are regarded as
a minute apparatus intended to permit the filtering through of
a highly aqueous urine, is to be entirely rejected. If the walls
of the glonaerular vessels are really permeable, and if the intra-
glomerular pressure P is much higher than the pressure in the
capsule, or commencement of the uriniferous tubules p, there
must be filtration, and the quantity of urine filtered must vary as
P-p. If this be allowed, it follows that if the value p is altered by
inserting a cannula connected with a manometer into the central
canal of the ureter, the flow of urine must cease after a certain
time, because the ratio P-p = 0. In fact, when this operation is
performed on the dog, the mercury column rises slowly till it
reaches 50-60 mm., and then remains stationary. At the same
time the renal pelvis dilates, the kidney becomes oedematous, and
after some hours the capsule of the kidney is seen to be ecchymotic
(Ludwig). This result is not, however, decisive in favour of the
theory of glomerular filtration, because it lends itself to a twofold
interpretation. It can be held with Ludwig, that when the
column of mercury comes to rest all formation of urine ceases,
and it may also be maintained with Heidenhain that when the
rise of the manometer is arrested the secretion of urine continues,
but that reabsorption from the tubules into the lymph channels
commences.
Another much simpler point, on which Ludwig laid great
stress, is that the efferent vessel of the glomerulus is always much
smaller than the afferent vessel. This constant fact must be
taken as the natural consequence of the heavy loss of water from
the blood during its passage through the glomerular vessels, owing
to the resistance there encountered, so that the quantity of water
that enters by the afferent vessels is larger than that which leaves
by the efferent. In any case, however, even on the assumption
that the glomerulus is a filter, it remains true that it is a filter
composed of highly sensitive living cells, and that its permeability
varies greatly with the alterations in the vital conditions of these
cells, as shewn by the striking effects of the temporary occlusion
of the renal artery. It is this physiological sensibility of the
glomerular walls that makes the rate of blood- flow more important
than the lateral pressure in the formation of urine.
In other words, the same theory applies to the function of the
vessels of the Malpighian glomerulus as was formulated above for
the formation of lymph from the common blood capillaries. (See
Vol. I. p. 519 et seq.) The only difference is that while in that
432 PHYSIOLOGY CHAP.
case the whole of the chemical components of the blood plasma
filter through, in the capillary glomeruli (which are more resistant,
and are strengthened by the internal layer of the flattened cells of
Bowman's capsule) only the crystalloid substances, which contain
all the essential constituents of urine, normally filter through with
the water. If the concept of a specific secretory activity of the
glomerular walls be excluded, we must logically exclude the idea
that anything more than water and the salts of the blood can be
excreted from the glomerulus, and must assume with Ludwig that
the normal glomerular filtrate is only a very dilute urine, containing
all the crystalloid components of the lymph, less its colloidal
constituents.
IV. When we reflect that the main function of the kidney is
to purge the blood from the products of the katabolic processes,
it is natural to conclude that this excretory activity is in intimate
relation with the composition of the blood, and that it undergoes
important modifications with the variations of the latter. Many
experimental data show this logical deduction to be correct.
Each time the water content of the blood increases or diminishes
there is an increase or diminution of the amount of water eliminated
in the urine. After copious draughts of water, the volume of
excreted urine reaches its maximum after 2-3 hours, and then
diminishes and becomes normal again after 5-6 hours (Falck).
The excess of water ingested is mainly eliminated by the kidneys,
a little being lost by cutaneous secretion (Ferber). After heavy
loss of water by profuse sweating, or severe diarrhoea, there is a
marked fall or temporary suspension in the excretion of urine, as
shown by a number of clinical observations.
These effects, which show the kidneys to be the chief regulators
of the water content of the blood, do not depend on changes in
the volume of the blood nor on the altered pressure at which it
circulates in the kidneys, for it has been shown, on the one hand,
that intravenous injection into a dog of the blood serum of the
same animal (Ponfick), and also of large quantities of defibrinated
blood (Albertoni), produces no marked increase in the excretion
of urine, as is the case with injection of water. On the other
hand, it is known that after free absorption of water by the
alimentary canal there is no rise, but rather, a fall of arteris
pressure (J. Pawlow). It therefore seems legitimate to conclude
that these effects depend upon the altered concentration of th(
blood, since we know that filtration through permeable membrane
(and therefore through the glomeruli) varies inversely with the
degree of concentration of the filtering fluid.
The urinary constituents normally contained in blood are even
more effective in promoting a secretion of urine. The injection of
urea, uric acid, and the inorganic salts of urine in sufficient
amount to increase the concentration of the blood, excite urinar
viii THE EXCEETION OF UKINE 433
secretion, i.e. act as diuretics (Segalas, 1823). Urea, which is
abundantly present in the blood, is one of the most potent diuretics,
just as we saw that bile is one of the best cholagogues. In experi-
ments with artificial circulation through the excised kidney, it is
necessary to add urea to the defibrinated blood in order to obtain
secretion of urine (I. Munk and Senator).
According to Ustimowitsch (1870), Heidenhain (1874), and
Griitzner (1875), the injection of a few grammes of urea into a
rabbit increases the formation of urine under normal conditions,
and reinstates it when arrested by section of the cervical cord.
The diuretic action of glucose when injected into the vein is
similar to that of urea. We have seen in Chapter V. that when-
ever the normal quantity of sugar in the blood exceeds certain
limits it escapes by the urine, carrying with it a large amount of
water, so that there is glycosuria associated with polyuria. In
diabetes mellitus this phenomenon may become very pronounced.
From this we may conclude that the kidney regulates not merely
the water content of the blood but also the amount of circulating
sugar, which (in excess of the normal) has a diuretic action like
urea, and probably acts by the same mechanism.
The diuretic action of the different sugars varies ; while glucose,
maltose, and lactose increase diuresis, laevulose, on the contrary,
has little effect, as shown by the experiments of Albertoni (1881-
1891). The increase of diuresis with glucose, maltose, and lactose
is due in his opinion to increased velocity of circulation and
dilatation of the renal vessels, perhaps also to a specific exciting
action which these sugars exercise upon the secretory renal
epithelium.
The diuretic action of caffeine is similar to that of urea. After
a brief delay or block of the urinary secretion, during which the
kidney shrinks, secretion begins again, and increases so as con-
siderably to exceed the normal value while the kidney expands.
Blood-pressure diminishes in the first stage ; in the second it rises,
and reaches or slightly exceeds the original level.
The action of digitalis is more complex, because it reinforces
and retards the beats of the heart, with simultaneous increase of
the tone of the vessel, so that arterial pressure rises. Under
normal conditions, therefore, its diuretic action is unimportant ;
with impaired cardiac activity, on the other hand, it does act as a
diuretic by the improvement in the conditions of the renal circula-
tion, due to increase of arterial pressure.
None of these facts militate seriously against the mechanical
theory, as regards the function of the glomerulus, in the above
sense.
Since the diuretic action coincides with increase of arterial
pressure, and ceases on its return to the normal, Limbeck's theory,
according to which diuresis depends upon the power of diuretics
VOL. II 2 F
434 PHYSIOLOGY CHAP.
to draw water from the tissues, and thus produce a hydraenric
plethora which raises arterial pressure and favours glomerular
nitration, is legitimate.
But this interpretation of the action of diuretics does not
correspond with the facts, because they are able to produce
diuresis without causing any rise of pressure. Thus Heidenhain
noted diuretic effects with intravenous injection of sodium nitrate
mixed with chloral hydrate, although no rise of arterial pressure
was visible on the manometer. Paneth afterwards saw that on
reducing urinary secretion by compression of the vas efferens,
transfusion of sodium nitrate solution or any other diuretic caused
& free 'flow of urine from the ureter, even if arterial pressure was
lowered.
According to Albertoni a marked secretion of urine also occurs
after the spinal cord has been divided on injection of sugar into
the blood. In the rabbit intravenous injection of sugar increases
the secretion from the kidneys without increasing arterial pressure.
Stefani and Cavazzani demonstrated that urea, when injected
into the blood, has a dilatator action on the vessels in general, but
acts more particularly upon those of the kidney. By artificial
circulation of isotonic salt solution to which 2 per cent urea had
been added, at constant pressure, the flow from the renal vessels
was increased by 78 per cent, from the vessels of the head by 37
per cent, of the liver by 32 per cent, of the limbs by 20 per cent.
These facts contradict the mechanical, and favour the secretory
theory, indicating that diuretics are specific stimuli of the activity
of the kidney cells. This view is strengthened by the fact which
Thompson ascertained in 1894, viz. that atropine (which suspends
or checks the activity of all glandular tissues) acts upon the
kidneys by diminishing urinary secretion and the amount of urine
excreted, i.e. it acts in the opposite sense to diuretics, although it
produces no fall in arterial pressure. Morphine acts in the same
way, but by lowering arterial pressure. On administering atropine
and morphine simultaneously, urinary secretion is arrested for a
certaiu time (15 to 45 minutes), although the renal circulation
continues, for when the flow of urine recommences it is absolutely
devoid of protein.
Many other serious objections might be raised to the second
part of Lud wig's theory, which assumes that the glomerular filtrate,
in passing through the uriniferous tubules, condenses gradually
by reabsorption of water, which is effected by an endosmotic
process in the walls of the tubules, until the filtrate assumes all
the chemical characters of urine.
If the whole of the urea, and, generally speaking, all the con-
stituents of urine, were really eliminated from the blood by
filtration through the glomeruli, as assumed by this theory, t\\o
impossible consequences would ensue, as Heidenhain pointed out : —
in THE EXCRETION OF URINE 435
•
(a) To obtain the 35 grms. urea excreted daily in the urine,
no less than 70,000 c.c. of fluid must filter through the glomeruli
of the two kidneys, under the most favourable computation,
according to which urea would be present in a maximal amount
of 0*05 per cent.
(6) Of this enormous quantity of nitrate, the no less enormous
amount of 68,000 c.c. must be reabsorbed by the uriniferous
tubules on the supposition that the day's urine is represented by
2000 c.c.
The absurdity of these conclusions is obvious when we consider
that a man weighing 75 kilos, has about 6 kgrms. blood, which
performs some three circulations per minute. On Heidenhain's
computation not more than 130 kgrms. can pass through the
kidneys in 24 hours, more than half of which (70 kgrms.) has to
filter through the glomeruli !
Another still more serious objection to the mechanical theory
is presented by the concentration or osmotic pressure of the urine,
which is almost always higher than that of the blood and lymph
circulating in the kidneys. Admitting the second part of Ludwig's
theory, i.e. that the glomerular filtrate gradually concentrates along
the course of the tubules, because the lymph in which these are
bathed is more concentrated than the urine, so that reabsorption
of water takes place by endosmosis, it is obvious that this reabsorp-
tion must cease so soon as the urine becomes isotonic with the
lymph ; in other words, the urine might reach the concentration
and osmotic pressure of the lymph and blood, but could never
exceed it. The formation of urine with a higher concentration
than the blood cannot be explained as a simple physical pheno-
menon, but necessitates the intervention of an active participation
of the secreting cells.
Dreser (1892) calculated the sum of this work for two special
cases. One urine secreted in a night to the. amount of 200 c.c.
had A = 2'3° C., while the blood of the same person gave A = 0-56° C.
According to Dreser's calculation, the work performed by the
kidneys in the secretion of this urine must amount to 37'037 kilos.
In a cat prevented from drinking for three days, Dreser obtained
a urine in which A = 4'72° C., while the blood of the same animal
showed A = 0'66° C. This difference in the freezing-point corre-
sponds with a difference of osmotic pressure =498 mm. water, or \
a pressure of 49,800 grms. per square cm. But it should be noted
that, according to the observations of v. Rhorer (1905). and
Galeotti (1907), this hypothetical value of the total osmotic work
of the kidney is in all probability much less than that which is
actually performed, assuming that the kidney functions by a
mechanism such as is assumed by chemists and physicists, i.e. as a
semi-permeable membrane. Supposing this concentration to be
performed osmotically by the walls of the renal tubules, we should
436 PHYSIOLOGY CHAP.
(on Dreser's calculation) have to admit the absurd conclusion that
they are capable of developing an energy six times greater than
that exerted by the human muscles, i.e. 8000 grins, per sq. cm.
So that if we hold with Ludwig that the glomerular filtrate is
concentrated and converted into urine along the renal tubules, we
are still bound to admit that this concentration is the effect not
of simple osmosis, but of a specific physiological activity of the
epithelial cells that line the tubes.
Another obvious objection to the mechanical theory is the fact
that while in all animals the blood serum is alkaline, the urine on
the contrary (except that of herbivora) is acid. Is it possible to
explain this difference of reaction by a simple process of filtration
and osmosis ? Some authors maintain that it is, since it has been
proved that when an alkaline fluid which (like urine) contains
mono- and dibasic phosphates filters through an inert animal
membrane, the filtrate is acid because the monobasic phosphates
filter through it by preference. Thus the filtrate collected from
Bowman's capsules may be acid although it comes from alkaline
blood. This explanation, however, does not hold in face of
Dreser's experiments (1885).
In order to decide the question he examined the micro-
chemical reaction of the various parts of the kidney in the frog,
using fuchsin (rubin-ty as an indicator, which loses its bright red
colour in alkaline solution. One to two hours after injection of a
concentrated solution of fuchsin into the lymph-sac of the frog the
acid urine secreted by the animal became red ; the kidneys were
colourless in the cortical region which contains the glomeruli,
while the tubules of the central part were stained red. From this
Dreser concluded that the filtrate of the glomeruli is alkaline, and
that the acidity of the urine depends on the secretory activity of
the epithelium of the convoluted tubules.
This result is confirmed by the use of diuretics. If the filtrat
of the glomeruli is alkaline, and becomes acid along the tubule
then the faster the urine passes through the tubules the moi
rapidly will the reaction of the urine approximate to that of tl
glomerular filtrate. This can be seen after the injection of
diuretic, e.g. caffeine ; the urine first becomes neutral, and eventi
ally is little less alkaline than the blood. We shall presently
whether the urine becomes acid in the tubules owing to tl
secretion in them of acid salts, or the reabsorption of alkalii
salts.
Albertoni and Pisenti, after administering a few c.c. of acetone
in aqueous solution (1 : 3) to rabbits, for several days in successioi
found serious alterations in the epithelium of the convolut
tubules only, while that of Bowman's capsule and of the straight
tubules was uninjured. If the acetone had been secreted aloi
with the water by the Malpighian glomerulus, it would, in the
vin THE EXCEETION OF UEINE 437
opinion, have been too dilute to produce such lesions in any part
of the urinary tubules; while if it had given rise to them, not
only the cells of the convoluted tubules, but also Bowman's
capsules, the straight tubules, etc., would have been implicated.
According to these authors the fact that the epithelium of the
convoluted tubules alone is attacked, indicates some special attrac-
tion of these cells to the above substance, which contradicts the
mechanical theory. ^
A last fact which shows the inadequacy of the mechanical
theory and the necessity for active intervention of the secretory
epithelial cells of the kidney, is the formation of hippuric acid,
which does not pre-exist in the blood, and which (in dogs at any
rate) is exclusively formed by a synthetic process in the kidneys,
initiated by the vitality of the epithelium of the urinary tubules.
(See Chapter VII. p. 393.)
V. These objections to the mechanical theory led to a revival of
Bowman's physiological theory, according to which the elimina-
tion of the specific constituents of urine (urea, uric acid, etc.) is
the effect of a specific vital activity of the epithelium of the con-
voluted tubules. But before this theory could be unconditionally
accepted it was necessary to obtain direct experimental evidence
that the vital activity of the epithelial cells of the convoluted
tubules and the ascending limb of Henle's loop (which, as we have
seen, possess all the morphological characters of specific secretory
cells) is expressed in an external secretion, i.e. by picking out the
urea, uric acid, etc., from the lymph, and excreting them into the
lumen of the tubules, and not in an internal secretion, i.e. re-
absorption of the water and part of the salts of the glomerular
filtrate, and return of them to the lymph, so as to condense the
filtrate, and bring about the concentration and osmotic pressure
proper to urine.
Unfortunately it is not possible, owing to the great diffusi-
bility and solubility of urea (the chief constituent of urine), to
follow its course through the kidney by micro-chemical reactions.
As regards uric acid, first Bowman and then v. Wittich described
the presence of crystals of this acid in the epithelia of the con-
voluted tubules. If these observations had been confirmed, they
would certainly have afforded a strong presumption in favour of
Bowman's theory ; but the later researches of Adolf Schmidt
(1890) showed that uric acid in a crystalline form is never seen
in the epithelial cells, even when, owing to ligation of the ureters,
the uriniferous tubules are charged with urates. On the other
hand, he saw that the urates in this case were never present in
the cavity of Bowman's capsule, but always along the tubule.
This fact is not, however, sufficient to demonstrate that the uric
acid is secreted by the cells of the tubules, because it is also
legitimate to assume that it is excreted by the glomeruli, and is
438 PHYSIOLOGY CHAP.
immediately driven out of the intracapsular space towards the
tubules by the stream of water, and then deposited in the lumen
of the canals in a semi-crystalline form after reabsorption of
water.
To clear up this difficult question Heidenhain had recourse
to the method of Chrzouszczewsky (1866). This consists in the
injection of sodium sulphindigotate (indigo -carmine) into the
blood, and subsequent detection of the colouring substance iu the
kidney, after fixing it, immediately after the animal's death, by
injection of absolute alcohol through the renal artery.
Indigo-carmine, when injected into the circulation of a rabbit,
is only eliminated by the liver and kidneys. A few minutes
after injection of 5 c.c. saturated aqueous solution the urine
becomes blue. On killing the animal and making sections of the
kidneys, they are seen to be the same colour, particularly towards
the points of the pyramids. In order to determine which cells
of the kidney expelled the pigment, Heidenhain arrested renal
secretion by a transverse section of the cervical cord, and then
injected indigo-carmine, killing the animal in 10 minutes, and
fixing the stain by injection of alcohol. On slicing up the kidney,
he found that the cortical part only was stained, while the medulla
was quite colourless. On examining the cortex under the micrc
scope, he saw that the blue colour was due to granules of the
pigment deposited in the lumen of the tubules, and also in the
striated cells which line them, while the intracapsular space
the narrow descending parts of the loops, and the collecting
tubules are entirely free of pigment.
If before injecting indigo-carmine (without inhibiting the
secretion by division of the cord) a circumscribed zone of the
kidney was treated with silver nitrate, only the outer layer of
the cortical part stained blue, while the rest of the kidney was
diffusely stained.
From these experiments Heidenhain concluded that the seci
tion of indigo-carmine is due to the secretory activity of the
striated cells of the convoluted tubules and ascending limbs of
Henle's loops, and assumed further that these cells, which have
the power of secreting an abnormal constituent from the blood,
must also be conceded the property of eliminating urea and the
other normal constituents of urine.
Serious objections to this conclusion were, however, raised bj
Pautynski, Henschen, and Sobieranski (1879, 1895, 1903). The}
noted that if the amount of indigo-carmine injected into tl
blood is in excess of that employed by Heidenhain, Bowman's
capsules and the glomerular epithelium also show a blue tin£
Heidenhain's data can therefore be reconciled with Ludwig's theoi
by admitting that the blue pigment is excreted by the glomerul
in very dilute solution, which is then concentrated in the tubule
vin THE EXCRETION OF UEINE 439
by reabsorptiou of water, so that the pigment is precipitated and
penetrates the striated cells of the convoluted tubules. In fact,
Sobieranski observed that in these cells the stain is most con-
spicuous near the inner surface, as though the pigment had
entered by the lumen of the tubules and not by the lymph
channels.
This view is confirmed, according to Sobieranski, by the effects
of injection with carmine, which, as it is less diffusible than the
sulphindigotate of soda, can more easily be followed in its passage
through the kidney. If the rabbit be killed 30-40 minutes
after intravenous injection of carmine, and the pigment fixed
by injection of absolute alcohol through the renal vessels, the
glomeruli stain red, and the epithelia of the convoluted tubules
are found to contain pigment granules in the part facing the
lumen, never in the basement membrane facing the lymph spaces.
According to Sobieranski, this shows that the carmine is taken up
by the striated cells on the side of the lumen, with the water they
absorb. But even if these facts minimise the value of Heiden-
hain's argument, they do not, in our opinion, prove as much as
Sobieranski claims, when he attempts to reinstate Ludwig's theory
by saying that the tubular epithelium is an apparatus for con-
centrating the glomerular filtrate— since this concentration is
due not to osmotic processes, but to a special physiological activity
of the cells, analogous to that of the intestinal epithelium as
expressed in an internal secretion.
In fact, we may suppose that the pigments injected into the
blood (both sodium sulphindigotate and carmine) are specially
eliminated by the epithelial cells of the uriniferous tubules,
and, when present in excess, by the glomeruli also ; and that
the internal part of these cells stains more than the basal part
may depend on the fact that the cells habitually expel the whole
of the substances which they take up from the lymph into the
duct as fast as they absorb them. Immediately after the death of
the animal, therefore, the whole of the substances already absorbed,
or able to be absorbed before the extinction of vital activity, are
collected in the inner portion of the cell, and are partly excreted
into the lumen.
In order to decide which of the two theories holds good, that
of Bowman and Heidenhain, who allow a physiological function
of external secretion to the epithelial cells of the tubules, or that
of Ludwig as modified by Sobieranski, who attributes to these cells
a physiological function of internal secretion, it was necessary to
discover some method for studying the function of the uriniferous
tubules apart from that of the glomeruli. Nussbaum (1878)
endeavoured to solve this problem by certain experiments on the
frog which may be summarised as follows : —
The amphibian kidney possesses a double series of vessels — that
440 PHYSIOLOGY CHAP.
of the renal artery from which the afferent vessels to the glomerular
tufts are given off, and that of the so-called renal portal vein,
which gives rise to the capillaries that ramify between the
tubules.
Experimenting with large frogs, Xussbaum found that the
secretion of urine is suspended by ligation of the renal arteries ;
but if urea be injected into the blood, secretion is resumed, show-
ing (according to this author) that urea is a diuretic, i.e. a secretory
stimulus which excites the activity of the epithelial cells of the
tubules, on which it is expelled from the blood along with a certain
quantity of water, independent of the function of the glonieruli.
If a solution of peptone, egg-albumin, or sugar be injected into
the blood of a normal .frog, the whole of these substances reappear
in the urine, where they can easily be demonstrated ; if the injec-
tions are repeated after tying the renal artery, and urea be added
to activate the secretion, none of these substances reappear in the
urine. From these results Nussbaum concluded that the function
of the glorneruli is to eliminate water, salts, egg-albumin, sugar,
and peptone, while the renal tubules have the task of eliminating
urea, uric acid, and the other specific constituents of urine.
These results of Nussbaum, which seemed to have finally
decided the controversy in favour of Bowman and Heidenhain,
lost much of their value by the control experiments carried out
by Adami in Heidenhain's own laboratory in 1885. He showed
that it was impossible in the frog to exclude the vascular circula-
tion of the glorneruli by simply tying the renal artery, because
certain branches of the ovarian artery anastomose with those of
the renal, so that even after tying the latter it is possible to fill
about half the glomeruli with red pigment on injecting carmine
into the aorta.
Adami further saw that if the kidneys are removed after
injection of defibrinated blood through the abdominal vein of
these frogs, and plunged into boiling water, the presence of a clot
of haemoglobin can be demonstrated inside Bow-man's capsule.
This clot consists of haemoglobin and protein, showing that the
injected blood must have poured through the glomeruli in con-
siderable quantities. Nussbaum's method is not, therefore,
adequate to determine the paths by which substances are excreted
from the kidneys.
In dogs, too, according to Adami, after tying the renal artery
and injecting defibrinated blood, escape of haemoglobin from the
glomerulus into Bowman's capsule can be detected.
Eibbert (1883) made another attempt to distinguish the
functions of the various parts of the kidneys. Starting from the
view put forward by Fick in his Text-book of Physiology, i.e. that
the urine formed by the glomeruli and convoluted tubules must
become condensed by reabsorption of water along the narrow
viii THE EXCRETION OF URINE 441
lirnbs of Henle's loops, and Bellini's straight tubules, he
attempted in the rabbit's kidney (which is the most suitable
because the renal medulla is not divided into pyramids) to cut out
the medullary substance as far as possible, in order to obtain
secretion from the cortical part alone, in the glomeruli and
convoluted tubules.
After longitudinally dividing one of the kidneys, scooping out
its medulla, and then suturing and replacing the kidney, he
excised the kidney of the opposite side. Rabbits thus operated on
survived only 3-4 days. On the second day the urine no longer
contained blood, and was less highly coloured and much more dilute
than normal urine. He held that this confirmed Fick's hypothesis ;
but in reality the greater dilution of the urine (the only result
arrived at) was obtained under conditions so far removed from the
physiological, that we fail to see how any definite conclusion can
be deduced from it, the more so as the urine must necessarily be
mixed with lymph.
Bradford's results on dogs (1892) have more weight. He
observed that after the extirpation of one whole and the half of
another kidney (so that not more than a quarter of the weight of
the total kidney substance was left in situ] the animal may live a
long time, but suffers from hydruria, i.e. it eliminates a much
larger volume of a urine far more dilute than normal urine, but
having almost the same total content of urea.
This result resembles that of Ribbert. The hydruria may be
interpreted as the effect of the larger quantity of blood circulated
through the remaining bit of the kidney, by which compensation
is effected, and exaggerated filtration through the glomeruli takes
place. But the function of the lost tubules could only be in-
adequately compensated or replaced by the few tubules left,
whether their function be one of external, or of internal secretion.
In the first case the percentage of urea in the urine would be
diminished by the insufficient excretion of urea by the tubules, in
the second by the insufficient absorption of water.
The same ambiguous interpretation attaches to the more recent
experiments of T. Schilling (1904), under Gerhardt's direction, in
rabbits that had undergone unilateral nephrectomy. He found
that these animals, when not hindered in drinking freely, are
capable of eliminating sodium chloride solutions administered by
the mouth as rapidly as normal animals. If, on the other' hand, the
water supply is limited, the salt is excreted at a lower concentra-
tion and more slowly than in the control animal under the same
conditions. But when compensatory hypertrophy is complete, the
one kidney is capable of eliminating salt under these circumstances
as if the conditions were normal. On the ground of these experi-
ments Schilling holds it probable that the single kidney, previous to
compensatory hypertrophy, is only partially capable of reabsorbing
442 PHYSIOLOGY CHAP.
the water that filters through the glomeruli. Obviously, however,
the opposite interpretation may also be sustained, i.e. that the
one kidney can only eliminate the salt to a less extent than the
normal, so that it is more slowly excreted and in a more dilute
concentration.
Bradford also found that on performing a still more radical
renal operation in which only one - sixth of the total bulk
of the two kidneys was left in a dog, polyuria properly so called
set in, i.e. the excretion both of water and of urea was increased.
This more active excretion of urea must be referred to the general
conditions which lead to an increased production of urea. The
animal, in fact, becomes rapidly emaciated, and soon perishes from
marasmus. This result indicates that normal general metabolism
depends on the normal functioning of the kidneys. But we are
still ignorant of the nature of the process by which renal insuffi-
ciency atfects metabolism so as to accelerate the katabolic
processes. We can only say that, according to some authorities,
the kidneys, like many other glands, are the seat of a specific
internal secretion which regulates metabolism, and which is quite
distinct from the supposed internal secretion (absorption) of water
ascribed by some to the convoluted tubules, in explanation of the
phenomenon of the formation of urine.
Many other workers have sought to distinguish the function of
the glomeruli from that of the uriniferous tubules. Lindemann
(1901) tried to eliminate the glomeruli by means of the vascular
circulation. He took advantage of the fact (see p. 424) that the
tubules are supplied not only by the blood from the capillaries of
the efferent glomerular arteries, but also directly by the blood
from the arteriae rectae, so that the whole of the blood circulat-
ing in the kidney does not pass through .the glomerular vessels.
Blood, therefore, still circulates through the kidney, though three
times as slowly as under normal conditions, after eliminating the
glomeruli, which makes it possible for the tubules to function
independently of the latter. In order to exclude the glomeruli, he
injected oil directly into the renal artery, on which' (as can be
seen under the microscope) the glomeruli, exclusively, are cut off
from the circulation, because the oily globules penetrate into the
rete mirabile. He found that a kidney thus partially embolised is
capable of functioning. It is able to pick up and excrete indigo-
carmine from the blood as well as a normal kidney, and also
secretes an urine, which, owing to the increase in its organic and
inorganic products, is more concentrated than the normal. Hence
the kidney thus altered is also capable of excreting the normal
constituents of urine. On the strength of these experiments
Lindemann came to the conclusion that the uriniferous tubules
are able to a certain extent to function independent of the
glomeruli, so that the excretion of water is not exclusively the
vni THE EXCBETION OF UEINE 443
function of the glomeruli, as claimed by the Bowman-Heidenhain
theory.
Some experimenters have made use of poisons, which attack
the separate parts of the kidneys electively, e.g. arsenic, aloiu,
chromic acid (Hellin and Spiro, 1897), or of circumscribed patho-
logical lesions, with the object of establishing a functional dis-
tinction between the elements of the kidneys. The able work
of Galeotti (1902) deserves special mention. He injected solutions
of 10 per cent sodium chloride or 30 per cent glucose solution into
the crural vein of dogs ; and then at different intervals took small
samples of blood from the carotid, and of urine from a catheter
fixed in the bladder. He determined the freezing-point and
electrical conductivity of both fluids, also for the urine the content
of organic and inorganic constituents, so as to obtain an approximate
notion of the work of the kidney. This work was carried out
partly on normal animals, partly on animals that had been
poisoned with corrosive sublimate (which particularly attacks the
uriniferous tubules), or cantharidine (which specially affects the
glorneruli). His fundamental results are, briefly, as follows : —
(a) The increase of osmotic pressure in the blood produced by
injection of hypertonic salt or sugar solutions excites the kidneys,
by a mechanism of which little is known, to increased activity, in
order to bring the osmotic pressure of the blood back to its normal
value. This tendency can be detected even in kidneys which are
so profoundly altered that they fail to attain their object. The
elimination of salt or sugar is begun, according to the principle of
least labour, by a marked excretion of water, which makes it
possible to secrete many molecules of salt or sugar without raising
the osmotic pressure of the urine much above that of the blood.
If the dog is prevented from drinking, the excessive output of
urine ceases, because the need of the animal to retain water is
opposed to the tendency of the kidney to eliminate it. Under
these circumstances a concentrated urine must be passed, in order to
eliminate the abnormal constituents of the blood. The secretion
of this urine occurs, however, with a much higher expenditure
of work on the part of the renal epithelial cells, and may
involve their exhaustion and degeneration.
(&) In the case in which, with unaltered function of the
glonieruli, the function of the epithelial cells is almost entirely
lost (corrosive sublimate poisoning), a copious urine of low
concentration is secreted ; vice versa, when the glomeruli are
damaged and the epithelia intact (cantharidine poisoning), a
scanty urine of higher concentration than the blood is formed.
Hence there is a certain independence in the function of the
glonieruli and the tubules, seeing that injury to either induces
different functional alterations.
(c) During filtration through the glomeruli the fluids on both
444 PHYSIOLOGY CHAP.
sides of the membrane are isotonic. This membrane is accordingly
permeable to .water and to electrolytes (at least to sodium
chloride) ; it behaves passively, and does not perform any
osmotic work.
(d) In its passage through the tubules the solution which was
at first isotonic with the blood becomes concentrated. The
osmotic equilibrium which prevailed at first between the two
solutions (blood and urine), separated by a semi-permeable
membrane (walls of the tubules), therefore alters, inasmuch as the
osmotic pressure of one of the solutions (urine) increases. The
work involved is performed by the tubules, which must therefore
possess the property of developing energy; for no analogous
phenomenon takes place with a passive, semi- permeable mem-
brane. This is the reason why on the death of the protoplasm
of the epithelial cells the higher concentration of the urine ceases
also.
(e) The fundamental question as to the mechanism by which
this increase in concentration is effected by the epithelial cells of
the uriniferous tubules, i.e. the controversy between the two
theories of Bownian-Heidenhain and Ludwig-Sobieranski, is not
solved by Galeotti, although many physiological and physical data
seem to him arguments in favour of the former.
Another method of cutting out the uriniferous tubules was
attempted by Bottazzi and Onorato (1904-5). By injecting a
solution of sodium fluoride into dogs' kidneys through the ureters
they proved microscopically that only the epithelia of the tubules
suffered, and not the glomeruli, since the poisonous solution did
not reach them. The following are the principal results of their
experiments : —
While in dogs operated on by unilateral nephrectomy the urine
secreted by the remaining kidney has a very high osmotic pressure,
sometimes twice as great as the normal, the urine secreted after
poisoning with sodium fluoride has a much lower osmotic pressure
than the normal. The fall in concentration seems to be approxi-
mately proportional to the intensity of the alteration of the
tubules ; it is certainly progressive ; the concentration is minimal
shortly before the death of the animal.
" The amount of urine eliminated from the poisoned kidney
depends on the degree of intoxication. If the epithelium of the
tubules is so much damaged that it becomes detached from the
walls, and blocks the lumen, the amount of urine secreted is
diminished : if, on the contrary, the epithelium is only functionally
injured and not detached, the amount of urine secreted is in excess
of the normal. This last fact can be interpreted in favour of
Bowman's theory. Bottazzi and Onorato assume that the
abnormal dilatation of the blood capillaries and excessive con-
gestion of the kidney poisoned with sodium fluoride cause a rise in
vin THE EXCRETION OF URINE 445
the blood pressure and rate of circulation, which produces increased
filtration through the walls of the uriniferous tubules. According
to these authors the water of the urine is eliminated not exclusively
from] the glomeruli, but from the tubules also (at least in some
part of the latter, e.g. in Henle's loops), an analogy with what
occurs in the sweat glands, where (as we shall see in the next
chapter) there is an abundant secretion of water without any
vascular apparatus similar to that of the renal glomeruli.
De Bonis (1906), a pupil of Galeotti, who partially repeated the
experiments of his master, and made use of Bottazzi's method for
eliminating the activity of the tubular apparatus, arrived at the
following results : —
The diuresis observed in dogs immediately after intravenous
injection of hypertonic solutions depends on the glomeruli, since
it takes place in kidneys in which the tubules had been injured.
On the other hand, this diuresis is probably in close relation with
the rate of circulation and pressure of the blood within the
glomerulus.
In the normal kidney the first period of diuresis, with low
concentration of urine, is followed by intense osmotic activity on
the part of the tubular epithelium, during which numerous saline
molecules are admitted into the glomerular filtrate. A rapid
increase in the molecular concentration of the urine then appears,
while the amount of urine simultaneously diminishes. In the
injured kidney, on the contrary, where the damaged epithelium is no
longer capable of performing so much osmotic work, the molecular
concentration of the urine is always low, and differs little from
that of the blood.
Hence we may conclude that the glomerulus also represents
an organ which regulates the osmotic pressure of the blood, since
while it normally passes a fluid which is hypotonic in comparison
with the blood, a fluid almost isotonic with the latter filters
through whenever the blood contains an excessive quantity of
osmotically active substances, i.e. each time the body feels the
need of clearing out these substances so as to bring the osmotic
pressure of the blood back to its normal value.
Accordingly we must regard the membrane which lines the
glomerulus not as a filtering membrane, the permeability of which
is invariable, but as a membrane that is variously permeable,
according to the needs of the body — as indeed must be admitted
for all living membranes.
Lastly it has been attempted to solve the fundamental problem
of the function of the two renal systems by artificial circulation
through the excised kidney, but without success, since it has so
far proved impossible to keep the isolated kidney sufficiently alive
for it to yield a secreted fluid similar to that which it excretes
normally. Pfaff and Vejnx Tyrode (1903) showed that defibrinated
446
CHAP.
blood is not adequate for the nutrition of the excised kidney. It
would be better, in experimenting on artificial circulation, to
employ perfectly normal blood prevented by appropriate treatment
from coagulating.
VI. The Eenal Circulation is certainly under nervous control,
so far as regards regulation of pressure and rate of blood-flow in
the vessels of the kidney by active constriction or dilatation of
the renal artery and its branches. The vasomotor system of the
kidneys is no less developed than that of any other vascular region,
Fio. 11V. — Roy's oncometcr (open and empty), for study of variations in volume of the kidneys.
Metal box, of approximately the same shape as the kidney, which opens by a hinge. Karli
half of the box contains two chambers, an outer A, and an inner II. The two upper chambers,
from the top of which the two-way tube E passes out, are clamped together by screw C. The
lower chambers are clamped by a similar screw. The box closes by the hook D, whidi
surrounds the hollow tube L, through which the renal vessels and the ureter pass out from
the enclosed kidney.
hence it is not difficult to recognise its effects by the eye. After
cutting the branches of the renal plexus that accompany the
artery as it penetrates by the hilum, paralytic dilatation of the
vessels of the external capsule can be seen. After excitation of
the renal plexus or spinal cord, the amount of blood flowing back
from the gland by the vein is diminished, and becomes blackish
with the character of venous blood, the secretion of urine being
arrested, while under normal conditions, when the kidney is
functioning, the blood remains, as we have seen, bright red like
arterial blood. Stimulation therefore produces constriction of
the renal vessels.
The most elegant method of demonstrating vasomotor action
on the renal circulation is undoubtedly that of the plethysmograph,
VIII
THE EXCEETION OF UEINE
447
which records the variations of volume that take place in the
kidney. By the application of this method Eoy (1881) devised
an ingenious apparatus which he called the oncogmph, as shown
in Figs. 117, 118, H9.
It is plain that the rapid variations of volume in the kidney
Fio. 118. — Oncometer as in Fig. 117 fitted up for experiment (cross section : proper size). Lettering
as in last figure. The dotted line H is a thin non-elastic membrane (calf's peritoneum), the
edges of which are clamped in each half of the box between the two chambers. A and /;,
the space between the membrane and the inner, lower chamber, is lilled with oil through the
opening, which is then closed by a tap F. The kidney G is then placed on the membrane
raised by the oil, so that the whole of the nerves and vessels with the ureter (which enter the
hilum enclosed in a fatty sheath) pass out at the aperture K without being compressed. The
box is then closed, and the space between the two membranes and the inner chamber of the
upper half is also filled with oil, through the tube e, which is closed by a tap. Every change
of volume in the kidney must now displace the oil, and is transmitted through the tube E to
the recording apparatus.
can only depend on variations in its vascular circulation ;
dilatation of the renal vessels produces increase, constriction of
the vessels decrease, in the kidney volume. In oncographic
curves, as in kymographic tracings from an artery, we can dis-
tinguish the oscillations of the sphygmic wave due to the cardiac
rhythm, the undulations of the second order due to the respiratory
rhythm, and occasionally the slower undulations of the third order
448
PHYSIOLOGY
CHAP,
which depend on variations of vascular tonicity (Traube-Hering
waves of blood.-pressure curves), but run in the opposite direction.
This signifies that the volume of the kidney diminishes when the
general arterial pressure rises, and increases when that falls,
because the rise of pressure is due to constriction of the peripheral
arteries, in which the renal arteries also take an active part.
This phenomenon can easily be produced artificially by
arresting artificial circulation in a curarised animal during the
experiment. The progressive asphyxia, which produces a diffuse
constriction of the small arteries and rise of general arterial
ff
FIG. 119. — Roy's oncograph for recording alterations in the volume of an organ. Half the proper
size. The faintly traced tube K is connected with the oncometer by a nibber tube. 1> is a
piston resting on the oil contained in the cavity Af. The oil cannot escape at the sides since
it is confined by a thin, flexible membrane E, which does not interfere with the up-and-down
movement of the piston. The recording line H is connected with the piston by the n>-'
which works through F, F. The screw C clamps the membrane near the piston between the
two ring-shaped surfaces N. The side-tube L which carries a tap is used for filling
api>aratus with oil.
pressure, causes a diminution in the volume of the kidney, becai
the renal vessels which participate in this constriction confine the
range of the renal circulation (Fig. 120). The same fact is
observed on stimulating the vasomotor centre in the bulb of
curarised animals, as well as on stimulating the splanchnics which
contain constrictor fibres for the renal arteries (Fig. 121).
On repeating these experiments after section of the branches
of the renal plexus by which the vaso-constrictors penetrate, the
opposite result is obtained, i.e. increase of kidney volume from the
passive dilatation of the renal arteries, due to the rise of arterial
pressure.
The vaso-constrictors of the kidney arise mainly in the dorsal
tract of the cord. In the dog the anterior "spinal roots from
VIII
THE EXCEETION OF UEINE
449
the 4th dorsal pair to the 4th lumbar (which correspond with the
second lumbar pair in man), contain vaso-constrictor fibres for the
kidney ; but most of them run in the anterior roots of the llth,
12th, or 13th thoracic pairs. These vascular fibres, after passing
through the ganglia of the sympathetic chain, run to the solar plexus,
and thence to the renal plexus by the splanchnics, or other paths.
When the anterior roots of these spinal nerves are excited by
rhythmic excitation of low frequency, the result is not constriction
but active dilatation of the renal arteries, expressed in a swelling
•of the kidney. This fact, discovered by Bradford, shows that
these roots contain vaso-dilator fibres to the renal arteries, besides
FIG. 120. — Increase of arterial pressure (P), and decrease in kidney volume (V), due to asphyxia
commencing at A. (J. Cohnheim and C. Roy.)
the vaso-constrictors. The former are excited by rapid rhythmical
stimulation, the latter by a slow rhythm. Both kinds of vascular
fibres seem to follow the same path till they penetrate into the
kidney.
It is still doubtful whether the spinal fibres from one side
innervate only the vessels of the kidney on the same side, or
partly those on the opposite side as well. It is also doubtful
whether the vagus contains fibres to the kidney. Certain experi-
ments carried out in Belgium by Masius (1888), in France by
Arthaud and Butte (1890), and repeated in Italy by Vanni
(1893), seemed to show that the vagi may exert a direct vasomotor
action on the kidneys, i.e. independent of the action of these
nerves on the heart and on arterial pressure. But this interpreta-
tion is excluded by the subsequent work of Walraweus (1896)
in Albertoni's laboratory. He shows : —
VOL. II 2 G
450
PHYSIOLOGY
CHAP.
(a) That stimulation of the vagus in the neck arrests renal
secretion by the inhibitory effect on the heart and consequent fall
of arterial pressure.
(&) That after atropinisation, excitation of the vagus has no
effect on renal secretion, which shows that it contains no vasomotor
or secretory fibres to the kidney.
Little is definitely known in regard to reflex vaso-constrictor
and dilator action in the kidneys, and nothing as to whether its
centres are localised in the cerebrospinal system, or situated
among the vasomotor centres of the other vascular regions.
FIG. 121. — Increase of arterial pressure (P) and decrease of kidney volume (V) from stimulation
of splanchnic at point marked on line B. (J. Cohnheim and C. Roy.)
While the foregoing and well-established evidence shows that
the renal circulation is regulated by a special system of vasomotor
nerves, there are so far no definite data to prove that the secretory
function of the kidneys is controlled by special trophic or secretory
nerves. Yet, on analogy with what we have seen in the study of
the other secretions, it must be taken as probable that the secretion
of urine is also under the direct control of the nervous system,
though we have at present no definite proof of this, just as a few
years ago (i.e. previous to Pawlow's work) we had no proof of the
existence of secretory nerves for the gastric secretion.
This argument by analogy has gained in value since Berkley
(1893) made the discovery that the nerve -endings of the renal
VIII
THE EXCKETION OF UEINE
451
plexus can be seen not only along the arterial vessels, but also
along the uriniferous tubules, and in Bowman's capsules. By
using Golgi's method for staining black with chromate of silver
he was able to follow the nerves of the renal plexus from their
entry into the hilum with the arteries to their peripheral destina-
tion. He saw that the nerves which accompany the vessels form
FIG. 122.— Nerves, ganglion-cells, and nerve-endings in kidney of mouse. (After Berkley.) 1.
Artery of medium size near hilum of kidney, with its nerve plexus ; A A, terminal fibres ; B,
diverging fibres ; E, nerve-ending. 2. Nerve fibres with nerve endings, surrounding a Bow-
man's capsule. Glomerulus visible inside capsule. 3. Cross-section of collecting tube and
longitudinal section of convoluted tubule, showing relation of nerve fibres and membrana
propria. Small blood-vessel lying near the collecting tubule. 4. Portion of convoluted tubule
in which the distribution of medium-sized nerve fibres arising from a ganglion can be followed.
5. Elongated ganglion cells on convoluted tubule, which appear to penetrate the membrana
propria.
rich gangliated plexuses along their course, which are distributed
both in the medullary and in the cortical layer as a very diffuse
network of nerve fibrils. The primary plexuses that accompany
the vessels (Fig. 122, 1} give off secondary branches and arborisa-
tions which surround the capsule of Bowman (Fig. 122, 2) with-
out, however, penetrating into it, while other ramifications are
452 PHYSIOLOGY CHAP.
distributed to the convoluted tubules, where they terminate in
the form of spherical dilatations or delicate fibrils, which penetrate
the basement membrane, and are presumably in connection with
the cement substance of the epithelial cells (Fig. 122, 3, 4, 5}.
These anatomical observations of Berkley were confirmed and
amplified later on by Azoulay (1894) and Pensa (1896), and more
particularly by the painstaking researches of T. D'Evant (1899),
who described four different kinds of nerve-endings in the kidney :
— (a) the terminations in the walls of the vessels ; (6) those of the
Malpighian glomeruli ; (c) those of the convoluted tubules ; (rf)
the free nerve - endings in the glandular parenchyma, which,
according to this author, have a centripetal function.
Evidently the function of these nerve fibrils can only be
trophic or secretory, and, is quite distinct from that of the vascular
branches.
As we have stated, however, no physiological experiment has
yet given indisputable evidence of the existence of secretory nerves
to the kidney. In 1835 Cl. Bernard affirmed that puncture of
the floor of the 4th ventricle produced polyuria, which is frequently,
but not invariably, accompanied by glycosuria. He explained the
different effects of puncture by the varying position of the
lesions. The point at which hepatic secretion of sugar is excited
lies rather deeper than that by which renal secretion of urine is
excited, but they are so close together that both are frequently
involved by the puncture, so that polyuria and glycosuria result.
Eckhard on repeating the experiments was unable to
accept this interpretation. In rabbits he found that simple
hydruria occurred very seldom. In these animals, on the other
hand, hydruria and glycosuria can be produced by mechanical,
electrical, and chemical stimulation of that part of the vermis of
the cerebellum which covers the rhomboidal sinus ; if the nerve
to the liver had been divided previous to excitation simple hydruria
resulted.
The clinical phenomenon of polyuria or hydruria (also known
as diabetes insipidus) shows the possibility of increased urinary
secretion independent of the internal secretion of the liver.
Diabetes insipidus has been observed in cases of inflammation anc
tumours of the medulla oblongata, and in cerebral disturbance, al
as an after-effect in attacks of epilepsy and hysteria (Ebstein).
The polyuria due to puncture is not caused by rise of arterial
pressure, since this does not vary, or falls slightly; it might
therefore arise from excitation of renal secretory fibres, as con-
jectured by Eckhard. But it is more probable, as Starling holds,
that it depends on the excitation of renal vaso-dilator fibres.
After division of the splanchnic nerve, the flow of urine at
once increases in the kidney of the side operated on, but this
increased secretion lasts a long time (3-4 hours), so that it cannot
vm THE EXCEETION OF URINE 453
be interpreted by a stimulation of secretory fibres due to section,
but must depend on a paralytic dilatation of the renal arteries,
similar to that produced after dividing the nerves that enter at
the hilum.
Lastly, if we admit the existence of secretory renal fibres (for
which there is some evidence in the histological facts discovered
by Berkley), it must be allowed that the system of secretory fibres
is able to function independently of the central nervous system.
In fact, it results from a series of experiments performed on frogs
by Bidder (1844), that in these animals the secretion of urine is
not arrested even when the spinal cord had been excised. The
same fact was also observed by Goltz and Ewald on a dog from
which they had removed nearly the whole of the cord in a number
of operations. We may therefore conclude that the secretory
nerves to the kidney belong to the sympathetic system, — which
entirely agrees with the histological work of Berkley.
As regards the reflexes transmitted to the kidneys, Spallitta's
results (3891) may be cited. He proved that ligation of one
ureter in dogs at a short distance from the renal pelvis often (in
3 out of 7 animals operated on) produced arrest of urinary secretion
in the kidney of the opposite side as well. In some experiments
this arrest lasted 40-48 hours, an abundant diuresis followed, and
sugar was found in the first urine excreted. These results agree
perfectly with clinical cases of reflex anuria due to renal calculi
with occlusion of one ureter (Tenneson, Carriere). Reflex anuria
or oliguria has also been observed in certain diseases of the testicles
(Nepveu), and in consequence of the surgical operations of vesico-
vaginal fistula (Jobert), and lithotomy (Aric6).
Vinci (1900-2) found in the dog that division of the spinal
cord between the third and fourth cervical vertebrae produced
total anuria, even if abundant diuresis had previously been
aroused by injection of glucose and lactose. Since he could not
detect any variation in blood pressure and circulation to account
for the anuria, he concluded that a renal centre must exist in this
part of the cord.
The clinical phenomenon of hysterical anuria (cf. the two
classical cases described by Rossoni ; Chap. VI. p. 361) is highly
important in relation to the hypothetical existence of renal secretory
nerves.
The well-authenticated fact of total suspension of the renal
secretion for long periods of time, which are unequal and occur
irregularly, lasting in the first case for a maximum period of 22
days, in the second for more than 30, seems to us incontrovertible
evidence for the existence of direct secretory nerves to the renal
gland. Having already described and estimated the effects of
hysterical anuria in regard to the vicarious excretory functions of
the gastro-intestinal system, we must now investigate its internal
454 PHYSIOLOGY CHAP.
cause or conditions, and endeavour to reconstruct the process by
which this absolute suspension of the renal secretion takes place.
Vulpian held that hysterical, oliguria was reflex in origin, and
caused by excitation of the renal vaso-constrictor fibres of the
splanchnics, which produces spasm of the renal arteries. But he
believed this explanation to be insufficient for hysterical anuria
(which may last for a very long time), and invoked the subsidiary
hypothesis of a reflex inhibition of secretion, capable of producing
arrest of functional work in the epithelia of the renal tubules.
Spallitta gave the same explanation of hysterical anuria.
To us this theory seems inadequate and improbable. It is
inadequate because in anuria the secretory function is suspended
not only in the renal tubules, but in the glomeruli as well ; im-
probable when we consider that the hypothesis of specific nerves
which directly inhibit renal secretion is contrary to all analogy.
We have no data showing the existence of trophic nerves to inhibit
secretion, while the existence of trophic secretory nerves, i.e. nerves
which on excitation provoke a copious secretory activity of the
epithelia, while their paralysis suspends it absolutely, is a matter
of classical demonstration, particularly for the salivary and gastric
secretions.
Long-continued anuria is one of the phenomena that make up
the syndrome of hysterical neurosis : there can be no doubt as to
its nervous origin. But while it is impossible to explain it as an
effect of activity of specific inhibitory nerves (which is always of
very brief duration), it is on the contrary easily interpreted as the
consequence of a paralysis of specific secretory nerves, hysterical
paralysis having been known to last for months and even years,
and to cease suddenly for some slight or unknown reason.
Admitting this as the only possible theory of hysterical anuria,
it is remarkable that such a paralysis of the peripheral
sympathetic centres and secretory nerve fibres of the complex
renal organ should be capable of suspending not only the specific
function of the tubular epithelia, but also that of the glomeruli,
which is in no way specific. This is a new and weighty argument
to add to those of Galeotti and De Bonis, against that theory b;
which the glomerular function is conceived as a merely physi
process of filtration.
The mechanical conditions of circulation in the glomeruli,
which evidently continue even after the supposed paralysis of
the secretory nerves, are inadequate to produce any excretion
of secretory fluid through their walls. This fact should be
remembered in endeavouring to explain why artificial circulation
through an excised kidney is not sufficient to produce a formation
of normal urine, even when urea is added to the blood circulated
(see p. 445).
VII. To complete the physiological study of the kidney as an
vni THE EXCEETION OF UEINE 455
organ of secretion, we need only examine whether the epithelial
cells of the convoluted tubules, which undoubtedly represent the
secretory part of the uriniferous tubules, undergo changes which
can be detected in the microscope in consequence of functional
activity, as compared with their cytological structure in the state
of functional rest. Owing to the continuous flow of urinary secre-
tion, the kidneys and their constituent cells can never, normally,
be in a state of absolute rest. Yet they are capable of being, and
often are, in a state of relative rest, under all physiological condi-
tions in which secretion is more or less reduced, e.g. in a protracted
absolute fast, and especially during hibernation, which for winter-
sleeping animals undoubtedly represents a periodically recurrent
physiological state.
Many physiologists and histologists have taken up this subject
(Nussbaum, Gibbes, Kruse, Lorenz, Tornier, and others) ; here we
can only refer to the more recent work of Sauer (1895), Trambusti
(1898), and E. and A. Monti (1900).
Sauer, in Heidenhain's laboratory, minutely described the
histological structure of the epithelium in the post - glomerular,
convoluted tubules of many mammals under various conditions,
and decided that the cells of these tubules are constantly provided
with the " brush-border " (orlo a spazzola), so that those authors
are right who regard this structure as a constant morphological
character, and those others wrong who regard it as an expression
of functional activity in the cells which exhibit it. According to
Sauer the resting tubules only differ from those which are in
secretory activity in having a narrower lumen.
According to Trambusti, on the contrary, this brush-border of
the cells of the post-glomerular tubules is not an integral part of
those cells. It is absent in rest, and is a temporary expression of
the function of the secreting cells. ' Below the "brush-border" there
is, according to Trambusti, another small striated border, which
he considers a constant character of the cell, and to which he
ascribes the greatest importance in the elimination of the secretory
products.
As between these two opposite conclusions, the results of
E. and A. Monti seem to us decisive, owing to their lucidity and
the strictly comparable physiological conditions under which the
experiments were carried out. They compared the renal tubules
of the marmot after prolonged hibernation (October to the end of
February), when the secreting function of the kidney must be
reduced to a minimum, with those of marmots that are awake and
fully nourished with milk. The difference in appearance of the
lumen and epithelial cells of these tubules is shown in Figs. 123
and 124. The uriniferous tubules of the waking marmot are
always more dilated than those of the hibernating animal, in
which the walls almost touch each other, and the lumen is nearly
456
PHYSIOLOGY
CHAP.
obliterated. The " brush-border," however, is plainly visible, and
does not differ perceptibly in the two animals. The same may be
said of the nuclei which are found in the resting state in both
animals ; they are situated in the basal third of the cell ; and are
spherical, with an indistinct reticulum, and large nucleoli which
vary in number. On the other hand the cell-protoplasm shows
marked differences. In the waking marmot it consists of a series
of nodulated threads which radiate from the axis of the lumen
(and cause the striated appearance) ; they are more distinct and
regular in the basal half, more fused, nodulated and interwoven in
the inner half which faces the lumen. In hibernating marmots
FIG. 123.— (Le
•- - ---'"
,ion through convoluted tubule of marmot during advanced torpor.
(R. and A. Monti.)
FIG. 124. — (Right.) Section of convoluted tubule of waking marmot, during functional activity
of renal epitbelia. (R. and A. Monti.)
the protoplasm exhibits the same thready and striated composition,
but it is much less apparent, because it is masked by a large
number of irregularly distributed granules, which differ in size
and in their affinity for stains. They are not fat droplets, because
they do not disappear on prolonged immersion of the sections in
xylol or oil of bergamot. It is therefore probable that they consist
of protein, destined to maintain the secretory work of the cell, and
that they accumulate when the function of the kidneys is reduced to
the lowest terms, as must be the case after prolonged hibernation.
These results of the brothers Monti are still more important
from the physiological point of view. To us they appear to give
histological evidence of the active intervention of the cells of the
convoluted tubules in the functions of the kidneys, and therefore
prove the inadequacy of the purely mechanical theory to explain
VIII
THE EXCKETION OF UEINE
457
the formation of urine. Of course this would not suffice to
decide between the theory of Bowman and Heidenhain and
that maintained by Sobieranski. Against this last theory, how-
ever, we may adduce almost if not quite all the objections made
by Heidenhain to Ludwig's contention. It further seems to us
improbable on the argument by analogy, in view of the fact that
the epithelial cells in all other tubular glands function as organs
of external secretion, although this does not preclude the possi-
bility of their simultaneously affecting the constitution of the
blood, by an outpour into the lymph of other special products of
an internal secretion. But this view, which was held by Brown-
Se'quard, Frankel, Meyer and others is far from proved, since both
the experimental facts and the clinical data on which it is
founded lend themselves to quite another interpretation.
Among the later histological researches into the activity of
FIG. 125.— Epithelium from pelvis of human kidney. (Kolliker.) 350 diameters. A, different
kinds of epithelial cells ; B, the same, in situ.
the kidney, we must cite the work of Gurwitsch (1902), who
investigated the elimination of indifferent aniline pigments on
frogs. He saw that they were excreted by means of vacuoles,
similar to those observed in Protozoa. The vacuoles, loaded with
pigment, gradually advance to the surface of the epithelial cells,
where they discharge their content into the lumen of the duct.
The latest experiments of Hober and Konigsberg (1905) on
pigment excretion by the kidneys has completely confirmed and
extended the results of Gurwitsch, so that histology also pro-
nounces decidedly in favour of the Bowman-Heidenhain theory.
VIII. The urine flowing from the collecting tubules of Bellini
is conducted from the renal pelvis by the Ureters, which are ducts
about the width of a goose-quill, 30-40 cm. long, with strong walls
consisting of an external fibrous coat, a middle coat of plain
muscular tissue (with two layers of longitudinal fibres, and one
thicker intermediate circular layer) ; and an internal mucous
coat with an epithelium composed of four layers in which the
cells differ in size and shape (Fig. 125).
458 PHYSIOLOGY CHAP.
Small branches of the renal artery pass from the pelvis to
the ureter, but other arterioles which come from the spermatic,
internal iliac, and inferior vesical arteries have an opposite course,
and run from ureter to pelvis. It is these branches that dilate
and develop after ligation of the renal artery, in order to re-
establish the renal circulation.
Nerve fibres pass in the ureter from above downwards from the
renal plexus, and from below upwards from the hypogastric and
spermatic plexuses. Ganglion cells are scattered at irregular
intervals between these nerve fibres.
The urine passes through the ureters less on account of gravity
than from the active peristaltic movements of their walls. On
exposing the ureter of an animal, or examining it in man, in cases
in which it has become accessible through laparotorny, it can be
seen that its contractions invariably begin at the extreme end of
the pelvis, and are peristaltically propagated towards the end near
the bladder. Antiperistaltic movements are normally never seen
in the ureters any more than in the intestine. It is natural to
suppose that the peristalsis of the ureters is excited by the urine
which trickles into them from the pelvis. In fact, after copious
draughts peristalsis is accelerated with the amount of urine
secreted. Urine, however, is certainly not a direct chemical and
mechanical stimulus, indispensable to the rhythmic movements of
the ureters, since the movements persist regularly even in ureters
cut out of the living animal with the kidneys, and sometimes even
in bits of isolated ureter.
If the ureter be stimulated mechanically or electrically, at
any point, the same phenomenon appears that we noticed in the
heart, i.e. waves of contraction are produced in both directions,
one peristaltic, descending towards the bladder, the other anti-
peristaltic, ascending towards the pelvis (Engelniann, 1869).
These are automatic rhythmical movements, similar to those of
the heart, propagated solely by muscular paths, independent of
ganglion cells and nerve fibres. They have been observed by
Engelmann even in isolated pieces of ureter taken from the middle
of the duct, where no ganglion cells can be detected under the
microscope.
The automatic rhythm of the ureters is sometimes regular (in
the rabbit three beats per minute can be counted), at other times
the movements occur irregularly, at others again they take the
form of groups separated by long pauses, which suggest the
periodic rhythm discovered by ourselves in the heart.
In cases of atrophy of the human bladder, it is usually found
that the vesicular orifices of the two ureters do not open simultane-
ously, that their peristaltic movements do not follow at regular
intervals, that the amount of urine that flows from them in the
time unit varies considerably. It has also been stated that the
vm THE EXCEETION OF UKINE 459
maximum quantity of urine flowing into the bladder at a single
peristaltic contraction does not exceed 4 c.c. (Zamshin, 1887).
It may be assumed by analogy with what takes place in the
heart and blood-vessels that the automatic, fundamentally
muscular rhythm of the ureters is regulated by the activity of the
intrinsic ganglia and the extrinsic ganglia, both in the sympathetic
system and in the cerebrospinal system. The experiments of
Protopopow (1897) in fact show that section of the great splanchnic
produces a delay in the peristaltic rhythm of the ureter of the
same side, while excitation of its peripheral end always produces
acceleration.
According to Protopopow's numerous experiments, the effect
of the various operations by which the circulation in the kidneys
and ureters is modified are variously expressed in the movements
of the ureters. To cite his principal results : —
(a) In acute asphyxia the contractions of the ureters become
more marked and frequent, as in all other plain muscular organs.
(6) When the secretion of urine ceases owing to ligation of the
renal artery, the contraction of the ureters becomes slower at
first, but subsequently returns to the same frequency as before,
(c) After occlusion of the aorta above the point at which the
renal artery is given off, there is in consequence of the anaemia a
marked slowing of the contractions of the ureters, which return to
the normal rhythm as soon as the aorta is reopened, (d) After
occlusion of the inferior vena cava above the mouth of the vas
efferens there is a marked and persistent acceleration in the
rhythmical movements of the ureters, due to the passive hyperaemia.
(e) With increased frequency of the drops of fluid which trickle
into the ureter its contractions are accelerated, more or less,
according to the nature of the fluid. (/) Ligation of the upper
part of the ureter immediately above the pelvis produces a
marked slowing, followed by complete arrest, of its movements.
(#) Atropine at first produces acceleration, afterwards retardation,
and finally arrest of the contractions of the ureter. (A.) Some
diuretics, i.e. diuretine and adonidine, do not modify the frequency
of the movements of the ureters; caffeine, on the contrary,
accelerates them in small doses, delays them in large.
The latest work on the movement of the ureters, carried out
by Lina Stern in Prevost's laboratory (1903), confirms the above
conclusions as a whole. Unlike Protopopow's results, however,
section of the splanchnic in the dog produced acceleration, and
stimulation of its peripheral end, inhibition of the movements.
According to this author the splanchnic contains both accelerator
and inhibitory fibres; the action of the latter is favoured by
atropine. According to Fagge (1902), on the contrary, stimula-
tion of the hypogastrics accelerates the movements of the ureters,
while stimulation of the splanchnics produces no effect.
460
CHAP.
IX. The ureters open into the bladder by two oblique orifices
that function .as valves, and close by the positive intravesical
pressure. While this impedes reflux into the ureters, the flo.w
of urine into the bladder, caused by the rhythmical peristaltic
movements of the ureters, which drives the fluid forward, and
opens the orifices, is not prevented.
The Bladder has an external serous or peritoneal coat which
lines only the posterior and upper half, an internal mucous
membrane which is covered with stratified epithelium similar to
FIG. 126.— Course of the muscular fibres of the bladder (Allen Thomson after Pettigrew, and from
nature), J. A. From the front. On the right side the superficial fibres are shown ; on the
left, the deep or circular fibres ; a, on the right side the median and most superficial bands of
the longitudinal fibres, showing slight decussation of the fibres ; a', those diverging somewhat;
a", the lowest, which pass much more obliquely ; the attachment of the longitudinal fibres to
the prostate is shown. On the left side, c the upper, <i the middle, c", the lowest set of
circular or deeper fibres ; s, the thickest and most transverse sets of three fibres forming the
sphincter ; p, right half of the prostate, the left half having been removed ; «, urachus
into which some of the longitudinal fibres are prolonged. B. From the back. Right side
shows superficial fibres ; left, the deeper fibres of the same kind, or intermediate fibres ; and
some of the circular fibres ; b, b, median, most superficial and strongest bands of longitudinal
fibres on right side ; V, more diverging fibres near middle of bladder; b', the most divergent
which surround entrance of ureters. On left side, c, d, and c" indicate the deeper circular fibres
passing round at various levels, and crossing with the deeper diverging fibres posteriorly : .-.
the most transverse fibres at the neck forming the sphincter ; u, the urachus ; u r, the ureters ;
the left half of the prostate has been removed to show the sphincter ; i; part of right vas
deferens and vesicula seminalis.
that of the ureters, and an intermediate muscular coat, which calls
for special consideration.
The muscular coat has an outer layer, the fibres of which are
mainly longitudinal, and are most distinct upon the anterior and
posterior surfaces of the bladder, and an inner layer of which the
fibres are mostly circular, which is thinner and irregularly reticu-
lated (Fig. 126). This distinction into two or three layers is,
however, only an anatomical device, since the fibres of which they
vni THE EXCEETION OF UEINE 461
are composed pass from one layer to another, and are united by
connective tissue. It is also an artificial distinction to regard
the longitudinal fibres collectively as one muscle, the detrusor
urinae, because the layer in which the fibres are mostly circular
must also contribute to the compression of the vesicular cavity
and increase of pressure within it, and thus to the expulsion of
the urine. The term "musculus detrusor" should comprise the
entire muscular coat of the bladder, which, as a whole, constitutes
a hollow muscle consisting of a tissue of plain fibres.
Anatomists are not agreed as to whether there is an internal •
sphincter of plain muscle at the neck or urethral orifice of the
bladder, independent of the layer of circular fibres described
above, and of the external sphincter of striated muscle ( Wilsons
or Guthries muscle} which is certainly under direct voluntary
control. Griffiths in England (1891), and Versari in Italy (1897),
devoted themselves to this subject. The former denied the
existence, not only for man, but for mammals and vertebrates in
general, of an internal sphincter vesicae independent of the circular
muscle fibres of the bladder. According to Griffiths, there is no
thickening of the muscular fibres near the urethral orifice to
justify the term " sphincter." But the question whether there
is or is not a sphincter in the bundle of circular fibres that
surrounds the neck of the bladder, ought not to depend on
whether this bundle is thicker than the circular layer of the
bladder or not, but on whether it has any special structure and
distinct physiological function. In regard to structure Versari's
researches seem to us exhaustive. He admits the existence of an
internal sphincter in both sexes, in adults as well as in infants
and children, for man as well as other mammals. According to
Versari there is a distinct formation shown by the peculiar
arrangement of the fibres, the greater compactness of the bundles
and their smaller size, and lastly by the smaller quantity of in-
terstitial connective tissue (Fig. 127). As regards specific function,
it is evident that while contraction of the muscular coat of the
bladder drives out the contents, and acts as a musculus detrusor
urinae, the tonic contraction of the internal sphincter prevents
incontinence of the bladder, i.e. escape of urine in the intervals
between one micturition and another. The function of the
sphincter is therefore diametrically opposed to that of the detrusor.
Some authors (Wittich, Lesser, Kosenthal) have concluded
from the fact that urine can be retained in the bladder even in a
dead body, that no tonic contraction of the sphincters is required,
but that the simple elasticity of the tissues is enough to prevent
incontinence. Eetention of the urine in a dead subject, however,
depends on the contracture which appears in the plain muscles
after the death of the nerve centres, and persists until the advent
of rigor mortis (S. Mayer), during which the bladder of the dead
462
PHYSIOLOGY
CHAP.
body can support the pressure of a column of about 900 mm. of
water before it. empties. Heidenhain and Colberg tried to demon-
strate the tonic action of the sphincter vesicae by introducing a
sound into the ureter as far as the neck of the bladder, and
measuring the pressure necessary to overcome the resistance of the
sphincter and to permit the penetration of fluid into the bladder,
which pressure is reduced after the death of the animal. But
it may be objected that the external pressure which is required
Fio. 127.— A. Section through bladder of young woman near the posterior wall of the curve. (Versari.)
Si, internal sphincter ; the bundle of circular fibres as seen in cross-section, with longitudinal
fibres from the detrusor urinae showing between. Se, external sphincter of striated muscle ;
fl,, fc., longitudinal and circular fibres, of which the muscular coat of the bladder is composed,
and which unite in forming the detrusor urinae. B. Section through bladder of girl near the
posterior wall of the cervix. (Versari.) Lettering as in A. Here the external sphincter is
not visible. It is nearly always incomplete and ill-developed in females, and is probably
absent in infancy.
in order to force the fluid into the bladder, sets up a reflex
which causes the sphincter to contract, or at least increases
its tonicity. The better demonstration of this normal tonic
activity seems to us to lie in the fact of the incontinence of urine
which is not uncommon in cases of disease of the brain or spinal
cord.
Since even in sleep, when the action of all voluntary muscles
is relaxed, the urine is normally retained in the bladder, it is clear
that the tonic activity to which the retention is due depends on
the internal sphincter of plain muscle, and not on the external
viii THE EXCKETION OF UEINE 463
sphincter of striated fibres, which is thrown into activity by
voluntary impulses only when it is necessary to delay evacuation
of the bladder, on feeling a desire to pass urine.
We must accordingly conclude that the urethral orifice of the
bladder is provided with an internal sphincter of plain muscle
(morphologically distinct from the circular layer of the bladder),
on the tonic contraction of which depends the retention, on its
paralysis the incontinence of urine.
While it is difficult to give experimental proof, we regard it as
probable that the tone of the internal sphincter of the bladder is
not constant, but varies with the tension of the bladder, and that
it is not automatic but reflex in character, i.e. determined by the
presence of the urine and the pressure which the latter exerts
upon the urethral orifice. The same opinion was clearly set forth
by Haller (1778) in the following words : — " Videtur urinae
modicam copiam in convexo vesicae fundo versus rectum
intestinum, sub urethra producto, facile et absque sensu colligi ;
deinde sphincterem incipere stringi, quando major nunc lotii copia
ad urethrae ostium adscendit, et eo majorem ejus musculi laborem
esse, quo altior super urethram nunc urinae columna est, suo
pondere urethrae ostium nitentis."
Experimental evidence for the theory of the retention of urine
by the tone of the internal sphincter of plain muscle has recently
been given by Eehfisch in I. Munk's laboratory (1897). In five
dogs which for over three months survived the severe operation of
removal of the prostate, including Wilson's muscle (external
striated sphincter), he saw that the urine was perfectly retained in
the bladder without a trace of incontinence. The same fact was
demonstrated on man by a very elegant experiment. By means of
a rigid catheter, he injected into the bladder of a man as much
boric acid solution as was required to fill it completely. On then
drawing the catheter back as far as the prostatic portion of the
urethra, so as to inhibit the contraction both of Wilson's muscle
which surrounds it, and of the compressor urethrae which surrounds
the membranous part of the urethra, he observed that the subject
was able not only to pass urine at will, but also to interrupt the
evacuation at any moment, by relaxation or contraction of the
internal sphincter (the only one he could control), so as to open or
close the urethral orifice.
Again : by other experiments on dogs Rehfisch was able to
show that, under ordinary conditions of closure of the urinary
canal, the external sphincter and the compressor urethrae play
only a subordinate part, the retention of the urine being specifically
the task of. the internal sphincter. After opening the peritoneal
cavity and exposing the bladder, he connected one of the ureters
with a manometer by a cannula which penetrated into the bladder,
and introduced into the other ureter the cannula of a syringe by
464 PHYSIOLOGY CHAP.
which fluid could be injected as required into the bladder. He
then ascertained the height to which the internal pressure of the
bladder must be raised in order to see the first drop of fluid flow
from the catheter introduced into the urethra at different depths.
He found that this pressure was approximately the same, either
when the catheter was pushed as far as the prostate, so as to
hinder the action of Wilson's muscle, or when it was in the free
part of the urethra, on which the action neither of this muscle
nor of the compressor urethrae was hindered.
While Versari restored to the internal sphincter its anatomical
function as distinct from that of the detrusor muscle, these
important experiments of Eehfisch prove it to be the chief
physiological factor in the closure of the urethra, and therefore in
the normal retention of urine.
X. The mechanism of micturition or urinary excretion is
certainly more complex than that of retention. It should be stated
at the outset that three different kinds of Micturition can be
distinguished and must be considered separately : — (a) wholly
involuntary micturition, (6) micturition produced by a desire to
pass urine ; (c) voluntary micturition, i.e. independent of desire.
Involuntary micturition is a constant physiological phenomenon
in infants at the breast, both in sleeping and waking ; it is often
observed in young children during teething, particularly when
tedious and painful ; it sometimes occurs with older children in
sleep, up to the age of puberty. In all these cases micturition is
a purely reflex, unconscious phenomenon, discharged by the great
excitability of the efferent and afferent nerves to the bladder, by
which the tone of the detrusor muscle, and therefore the tension
of the bladder walls, is reflexly exaggerated. It is probable that
in these cases the tone of the internal sphincter increases simul-
taneously, so that there is a conflict between the two antagonist
muscles, the sphincter which closes the urethral orifice, and the
detrusor which tends to open it by an outward pull (as assumed
by Kohlrausch), which is due more particularly to the contraction
of the fibres inserted radially between the muscular bundles of the
sphincter, to which Versari has lately called attention. Since the
struggle ends with emission of the urine contained in the bladder,
the expulsive force of the detrusor ultimately prevails over the
retentive force of the sphincter.
Experimental confirmation of this very simple mechanism of
involuntary micturition is afforded by an experiment of Mosso and
Pellacani (1882) on chloroformed and curarised dogs. They
divided the ureter close to the neck of the bladder, opened the
abdominal cavity, introduced a cannula into one of the ureters
joined up with a Mariotte's bottle, and determined the pressure
necessary to obtain a flow from the urethra. The tone of the
detrusor muscle was then artificially raised by mechanical,
vrii THE EXCEETION OF UEINE 465
electrical, or thermal stimulation of the bladder walls, after which
the pressure necessary to produce incontinence was again deter-
mined. They found that increase of tone in the detrusor was always
under these conditions associated with increase of tone in the
sphincter, so that more pressure was necessary to force the urine
through it.
The involuntary micturition of fright, formerly interpreted
as the effect of a sudden paralysis of the sphincters, may result
from an analogous process. Mosso and Pellacani noted in support
of this view that when a dog is frightened by shouts, or sudden
pain, there is an increase of tone in the sphincters, expressed in
the fact that a much higher pressure than the normal is required
to force fluid through the urethra. This result can, however, be
explained by a reflex contraction of the sphincter, due to the
injection through the urethra ; it does not seem to us to prove the
contention of the authors.
In the adult also, owing to the preponderance of the detrusor
activity over that of the internal sphincter, involuntary micturi-
tion would take place each time that excessive accumulation of
urine, or increased activity of the nerves to the bladder, raised
the vesical tension beyond a certain point, if the sphincter were
not (in order to retain the urine within the bladder for a certain
time longer) reinforced by the active voluntary intervention
of Wilson's muscle, and of the compressor urethrae, as well as of
the musculi bulbo-cavernosi, to which is associated the action of
the sphincter ani. When these coadjuvants are inadequate, in-
voluntary micturition takes place, as not infrequently occurs in
young children.
The mechanism of the micturition which is aroused by con-
sciousness of distension in the bladder and irritation in the region
of the vesical orifice, leading to an imperative desire for relief, is
more complex. The origin of these sensations must first be
examined.
They are certainly not due directly to the tension of the
bladder, because the amount of urine passed under different con-
ditions is very variable, and is not in ratio with the strength of
the desire. There may often be an urgent need to micturate,
when very little urine is present in the bladder. This leads
to the conclusion that the tone of the bladder wall is very vari-
able, and that the need to micturate depends less on the passive
distension of the bladder than on its active reaction to the contents,
i.e. the pressure of the urine within the bladder.
In this connection the researches of Mosso and Pellacani on
the great reflex excitability and variable tone of the muscular
coat of the bladder are interesting. It is susceptible to mental
influences, whether these are accompanied by changes in arterial
pressure or not. At constant pressure the bladder may contain
VOL. II 2 H
466 PHYSIOLOGY CHAP.
a very different volume of fluid, and the need of micturition
always arises under the same pressure (in a dog at a pressure of
20 cm., in a girl at a pressure of 18 cm. water) whatever may -be
the volume of fluid contained in the bladder. These authors
concluded that micturition is excited by the pressure to which
the walls of the bladder are subjected, and not by the varying
degree of their distension.
If when the desire to micturate arises, the act of evacuation
is delayed by the voluntary mechanism above described, the
desire may lessen, or even disappear after a certain time. This
phenomenon depends on a lowering of tone in the bladder and
the consequent reduction of vesical pressure, although the quantity
of urine has not been diminished, but even increases, — whicl
confirms the variability of the tone of the bladder and the
dependence of the desire to micturate upon vesical pressure, i.t
on a certain active reaction of the muscles of the bladder to its
contents.
When, on the contrary, the need to micturate increases and
becomes imperative, the flow of urine must be given free vent,
and may in this case be termed voluntary, but only because it
commences with the relaxation of Wilson's muscle (external
sphincter), i.e. with the removal of the obstacle .opposed by the
will to the action of the detrusor urinae. It is true that in order
to reinforce the expulsory effort of the latter, and to empty the
bladder as completely as possible, abdominal compression, i.e. the
repeated voluntary contraction of the abdominal muscles and
diaphragm, plays an active part. This intervention, however,
is not necessary, because the detrusor is in itself capable (after
the animal's body has been opened) of developing sufficient force
to hold up a column of water 1*5-2 m. in height (as observed by
Mosso and Pellacani), and micturition normally takes place easily,
even if more slowly, without any intervention of abdominal
compression, i.e. with no perceptible modification of respiratory
rhythm.
The mechanism of micturition aroused by consciousness of
tension in the bladder accordingly differs from that of involuntary
micturition only in the previous, voluntary relaxation of the ex-
ternal sphincter. On this assumption both involuntary micturition
and that preceded by the desire to micturate would be essentially
reflex acts, independent of the direct exercise of the will.
This theory, which at first sight appears simple and satisfactory,
was overthrown by an ingenious experiment of Rehfisch.
By perfecting a method already employed by v. Zeissl in the
study of vesical iunervation (infra), Rehfisch introduced a catheter
into the human bladder, provided with a two-way tap by which
boracic acid solution could be injected in order to increase the
content and distension of the bladder. By a turn of the tap he
VIII
THE EXCEETION OF UKINE
established communication between the bladder and a Gad's metal
manometer which recorded the intravesical pressure on a revolving
drum. The subject was then invited to micturate, and the urine
which flowed from the urethra down the side of the catheter
was run into a filter communicating with a bottle connected
at atmospheric pressure with a Gad's plethysmograph, which re-
corded the flow of urine on the same drum. The arrangement is
shown in Fig. 128. By this ingenious method Eehfisch was able
Fia. 128. — Apparatus used i by Rehflsch to study micturition in man. The catheter K, introduced
into the bladder B, communicates either with the syringe S or the manometer M, according as
the two-way tap D is set in position /. or II. The funnel T receives the urine which flows
from the urethra down the side of the catheter, and leads it through tube C to flask F, whence
the pressure is transmitted by tube L to the plethysmograph V. The manometer records the
curve of vesical pressure A, B, on the revolving cylinder, and the plethysmograph the volume
curve of the urine C, D.
to compare the pressure curve with that of vesical evacuation,
during voluntary micturition.
If the opening of the sphincter, as expressed in the rise of the
lever, always coincided with the moment at which pressure in the
bladder became maximal, this would show it to be the passive
effect of the increased tension in the bladder, and would be an
experimental demonstration of the theory by which micturition
468 PHYSIOLOGY CHAP.
is made to depend on the predominance of the detrusor over the
sphincter. Bat in nine experiments Rehfisch was able to show
that the opening of the urethra occurred five times when the
curve of vesical pressure was on the down-grade, three times when
on the up-grade, and once when it had reached its summit. He
also saw that the pressure in the bladder was not maintained
at a constant level during the time of evacuation, but almost
constantly diminished.
These results contradict the hypothesis that it is the pre-
ponderating force of the detrusor which opens the sphincter and
keeps it open for the entire period of micturition. They show,
on the contrary, that the moment of opening the urethra or re-
laxing the sphincter is independent of the contraction of the
detrusor, although the latter precedes the former by a shorter or
longer period. We may therefore conclude that in the mechanism
of micturition as incited by desire, the lowering of tone or active
voluntary relaxation of the internal sphincter of smooth muscle
is a main factor in the process, and that instead of opposing, it
promotes the contraction of the detrusor.
Hanc (1899) obtained confirmation of this theory by experi-
menting with curarised dogs, on which he simultaneously recorded
the pressure in the bladder and the amount of flow from the
urethra during the reflex excited by stimulating the sciatic. At
the beginning of each experiment the bladder was filled with a
constant quantity of tepid water. He concluded from the ratio
between intravesical pressure and the flow of urine in thirty-two
experiments that they are independent of each other, i.e. that the
contraction of the detrusor and the expansion of the sphincter are
two distinct phenomena due to the activity of two separate nerves.
The animals being curarised, all active intervention of the will is
excluded in this kind of reflex micturition.
If the animal be put under morphine before stimulating the
sciatic, the contraction of the detrusor persists, but there is nc
longer dilatation of the sphincter, so that the evacuation of the
bladder is premature. This is probably due to the fact that the
two muscles are under the tonic influence of two distinct spins
centres of antagonistic action. Chloral hydrate also acts like
morphine, but weakens the reflex of the detrusor as well. Atropine
and cocaine weaken both reflexes. Strychnine produces the opposite
effect, but in a variable degree. The same holds good for muscarine.
It is also possible, as we stated above, to perform the act of
micturition perfectly, independent of any more or less urgent
desire, i.e. without the bladder being in such a tonic or contracted
state as to arouse the sense of repletion or tension. For instance,
micturition can be repeated a few moments after evacuation of the
bladder.
This form of micturition is purely voluntary, and quite distinct
vm THE EXCKETION OF UKIKE 469
from what we have been considering. Few physiologists since
Kohlrausch (1854) have taken it into serious consideration.
Kohlrausch, in order to explain micturition without, or previous
to, desire, assumes that active intervention of the diaphragm and
abdominal muscles is necessary, in order by compression of the
intestines to lower and flatten the top of the bladder, and to pro-
duce the contraction of the detrusor. This muscle, by the fibres
inserted between the bundles of the sphincter, would act in a less
oblique direction, almost vertical to the fibres of the antagonist
muscle, and would thus succeed in overcoming the resistance and
opening the orifice of the urethra. Such an interpretation, how-
ever, appears to us to be totally erroneous, since it subordinates
the phenomenon to the active intervention of abdominal com-
pression. We have frequently convinced ourselves that it is .easy
to micturate a few minutes after emptying the bladder, without
any modification of respiratory rhythm by which compression
could be exerted. Moreover, in this case the urine is evacuated
by a process which differs somewhat from that above. The
micturition caused by desire takes place directly the obstacles
(voluntary contraction of external sphincter, and reflex tonic
contraction of internal sphincter) which prevent the escape of the
urine are removed. Micturition without desire is, on the contrary,
preceded by an obscure sense of slow relaxation of the internal
sphincter, followed by a very long pause before the flow of urine
commences, during which a not unpleasant sensation of titillation
is felt near the orifice and the upper part of the urethra. That
Valentin is in almost complete agreement with this description of
micturition without desire is shown by the following passage : —
" Si mingendi consiliuui coepimus, musculum clausorium vesicae
relaxatum esse primo sentimus, turn vero intervallum longius
breviusque intrat, quo lotium nondum defluit, denique lotium
ipsum ejicitur." Nothing is omitted here except the sense of
titillation previous to the passing of the urine.
The only possible interpretation of the phenomena which
accompany micturition without desire appears to us to be as
follows : — By the cerebral motor centres we voluntarily inhibit
the action of a spinal centre which exerts a tonic action upon the
internal sphincter of the bladder ; the relaxation or expansion of
this muscle permits a few drops of urine to trickle into the first
part of the urethra, which act on the sensory endings of the
urethral mucosa, and arouse the sense of titillation ; this sensation
then produces reflex contraction of the detrusor, which is followed
by evacuation.
So that in this case also (if our interpretation be justified)
micturition is not entirely voluntary, but is a process which,
although initiated by the will, develops as a reflex act, independent
of the influence of the higher centres.
470 PHYSIOLOGY CHAP.
Micturition without desire, therefore, differs from that caused
by desire only in the fact that the dilatation of the urethral orifice
by voluntary relaxation of the internal sphincter precedes instead
of following the reflex contraction of the detrusor.
XI. It is very important that we should complete the study
of micturition by reviewing the experimental evidence for the
innervation of the bladder, since it substantially confirms our
theory as to the mechanism of micturition in the above three
different cases.
From a number of experiments on dogs, cats, and rabbits, we
may assume positively that the bladder is supplied by two sets
of nerves. The first set are derived from the lumbar nerve-roots,
particularly from the third and fourth pairs, the fibres of which
run in the rami communicantes to the lumbar part of the sym-
pathetic chain, where with the mesenteric nerves (upper, middle,
and lower) they join the inferior mesenteric ganglion, and finally,
by the hypogastric nerves, reach the hypogastric plexus and the
bladder.
The second set of nerves to the bladder originate in the roots
(both anterior and posterior) of the sacral nerves, especially of the
first to the second pair, from which two branches are given off,
known as the nervi erigentes of Eckhard, which run straight to
the hypogastric plexus, and thence to the bladder and the corpora
cavernosa of the penis (see Fig. 106, p. 371). So that all the
nerves which run from the cerebrospinal axis to the bladder pass
in two distinct nerve-trunks, the hypogastric and the nervus
erigens. Both, as we shall see, innervate the detrusor, and also
the internal sphincter of plain muscle. The external sphincter
and other striated muscles of the urethra are innervated by the
nervus pudendus (Griffiths).
The vesical nerves are particularly abundant at the neck of
the bladder, where they form plexuses in which ganglion cells are
included (E. Mayer) : they terminate partly in the blood-vessels
(vasomotor nerves), partly in the muscle cells (motor nerves to
muscles), and partly penetrate between the layers of the epithelium
(sensory nerves).
Budge (1864) was one of the first to investigate the motor and
sensory nerve -paths to the bladder. He saw that the nerves
coming from the anterior sacral roots are able to excite contraction
of the bladder directly, and also reflexly (by stimulation of corre-
sponding posterior roots). Stimulation of the lumbar sympathetic
also produced contraction of the bladder, but this was always
accompanied by signs of pain in the animal. Stimulation of the
central cord of this nerve produced the same effect. Section of
the rami communicantes so as to interrupt all connection with
the cord, but not with the hypogastric nerves and plexus, had,
according to Budge, no effect on the bladder. From this he
viii THE EXCEETION OF UKINE 471
concluded that the sympathetic contains sensory fibres to the
bladder which reach the cord by the rami communicantes. Having
noted that other nerves (trigeminus, splanchnic) which cause pain
do not increase intravesical pressure, he concluded too hastily that
only the sensory nerves coming from the bladder are capable of
acting reflexly upon it.
Oehl (1865-69) obtained contraction of the bladder (as
deduced from the increase of intravesical pressure) in dogs by
exciting the intact vagus in the neck, or the central end of the
cut nerve, or even its peripheral end, although in the last instance
the effect is minimal. From this he concluded that the vagus
contains sensory as well as motor fibres in direct or indirect con-
nection with the bladder. Kehrer (1867), however, on repeating
Oehl's experiments, with the peritoneum opened so that he could
observe the bladder directly, saw that the stimulation of the vagus
produced no effect even when transmission of all other movements
was prevented. He, therefore, denies the connection of the vagus
with the bladder, a negative conclusion which was also reached
later by Sokowin, Nussbaum, Nawrocki.
Bert (1869) amended Budge's conclusion that only the sensory
nerves arising from the bladder were capable of acting upon it
reflexly. According to him, centripetal excitation of the sciatic,
median, and infraorbital nerves constantly produces a contraction
of the bladder.
Sokowin confirmed this result, and found the same for other
sensory nerves (crural, splanchnic), but he added that all the
reflexes ceased after ablation of the cerebral hemispheres of the
animal. He concluded that sensory nerves which do not arise in
the bladder act reflexly upon it, inasmuch as they arouse pain.
The vagus was the only exception, since he was unable to confirm
Oehl's results.
In a second series of experiments Sokowin found that stimula-
tion of the centripetal fibres of the hypogastric nerve acts reflexly
upon the motor fibres of the hypogastric on the other side, by
means of the inferior mesenteric ganglion, which in this case
functions as a reflex centre. He further saw that centripetal
stimulation of the posterior sacral roots produces reflex contraction
of the bladder, which ceases in the cat after division of the cord
at the level of the fourth lumbar vertebra. ITussbaum (1879), in
Nawrocki's laboratory, confirmed these important results of Sokowin
as to the direct and reflex innervation of the detrusor muscle.
Subsequently Nawrocki and Skabitschewsky (1891) adduced fresh
proofs from a more extensive series of accurate researches, and
came to the following conclusions : —
(a) Every sensory nerve of the body produces contraction of
the bladder by the mediation of the brain, (b) Excitation of the
sensory spinal nerves to the bladder is carried across the cord to
472 PHYSIOLOGY CHAP.
the corresponding motor nerves to the bladder, (c) In the trans-
mission of excitation from the sensory sympathetic nerves to the
motor nerves of the bladder, the inferior mesenteric ganglion acts
as the reflex centre.
All these investigations concern the innervation of the
detrusor muscle exclusively, because they were carried out by the
introduction into the bladder of a cannula or catheter connected
with a water manometer, which threw the sphincter of the bladder
out of play. Further, the motor nerves to the bladder were almost
always stimulated reflexly, from the central end of the divided
sensory nerves. The effects on the detrusor and sphincter of direct
excitation of the motor paths to the bladder had next to be
studied, to see if they are identical or antagonistic, in accordance
with the function of the two muscles.
This most important problem was ingeniously solved by von
Zeissl (1893). He confined his experiments on curarised dogs to
studying the effects of excitation of the hypogastric nerves and
the nervi erigentes on the detrusor and on the sphincter. With
this object he employed a method similar to that which Eehfisch
subsequently modified so as to render it applicable to man (see
Fig. 128, p. 467). After laying open the peritoneum, he tied one
ureter, and connected the other with a pressure-bottle by means
of which the bladder could be filled. He then interrupted the
communication of the bladder with the bottle and brought it into
relation with a mercury manometer, which recorded variations in
tone (contraction or expansion) of the detrusor on a revolving
cylinder. Lastly, he tied a tube into the urethra, and connected
it with a plethysmograph, by which the amount of flow from, the
bladder is recorded on the drum. On comparing the two curves
obtained from stimulation of the hypogastric or the erector nerve,
the action of these nerves on the two antagonistic muscles of the
bladder can be computed.
The following conclusions appear from von Zeissl's work : —
(a) The nervus erigens contains motor fibres to the detrusor
and inhibitory fibres to the sphincter, because its peripheral
stimulation causes contraction of the former, and expansion
(relaxation) of the latter. (6) The first effect is quite independent
of the second, since it always precedes it by a greater or less interval,
so that the escape of fluid from the bladder cannot be regarded as
a direct effect of vesical contraction, (c) If the contraction of the
detrusor is hindered by substituting a glass bell-jar for the wall
of the bladder, stimulation of the nervus erigens only produces
dilatation of the sphincter, showing that this effect is not passive,
but depends on specific inhibitory or diastolic fibres contained in
the excited nerve, (d*) The hypogastric nerves contain motor
fibres to the sphincter, and moderator nerves to the detrusor, since
their peripheral stimulation arrests the continuous flow of urine
vin THE EXCKETION OF UEIKE 473
from the urethra, produced artificially by surcharging the bladder
with fluid, while a pressor effect upon the bladder walls seldom
makes its appearance.
In a second set of experiments (1894), von Zeissl, experiment-
ing not with curarised dogs, but on such as were merely under
morphine, obtained results which were wholly in agreement with
the preceding. He also performed a new series of experiments to
determine the reflexes of the sphincter and detrusor, by excitation
of the central end of certain sensory nerves (sciatic, ulnar, median,
phrenic, splanchnic, and vagus). The method employed was
simpler than the above. In curarised male dogs he introduced a
glass tube right into the bladder, or to the end of the membranous
urethra, according as he wished to bring out the effect on the
detrusor, or the sphincter.
This tube was brought into direct connection with a water
manometer, which recorded on a revolving cylinder the flow from
the bladder consequent on excitation of the nerve. The peri-
toneum was not opened.
Stimulation of the central end of the above nerves always
produced contraction of the detrusor and expansion of the
sphincter. The sole exception is the stimulation of the central
end of the vagus, which has no effect on the bladder, while, like
the other nerves, it causes a rise of arterial pressure. From this
we may conclude that the vesical reflexes produced by excitation
of the sensory nerves are transmitted by the motor paths in the
anterior sacral roots, which make up the nervi erigentes.
The later work of Courtade and Guy on (1896), while it mainly
confirms von Zeissl's results, has little intrinsic value, since it was
carried out by a less perfect method, and under conditions farther
removed from the physiological.
The more extensive researches of Langley and Anderson (1896),
on the innervation of the viscera, do, on the contrary, confirm
both the results of Nawrocki and Skabitschewsky, and those of
von Zeissl, which are also sustained by the later experiments of
Eehfisch and Wlassoff (1900).
Von Zeissl afterwards (1902) continued his researches on the
innervation of the bladder, using the same method as before. He
found that central stimulation of the sciatic (even when all
increase of pressure in the bladder was excluded) induced partial
evacuation by opening the sphincter, which, however, might be due
solely to the nervi erigentes. If water is made to flow continuously
through the urethra central stimulation interrupts the flow, even
after the hypogastrics have been divided. This, however, is due,
not to the erigentes, but to the nerves which supply the striated
sphincters (external sphincter, compressor urethrae), the endings of
which, like those in the sphincter ani, are only paralysed by an
excess dose of curare.
474 PHYSIOLOGY CHAP.
As regards the central organs on which the movements of the
bladder depend, it can be gathered from the above that there must
be cerebral, spinal, and sympathetic centres : the first come into
play in voluntary micturition and that excited by the feeling of
vesical tension ; the second in involuntary and purely reflex
micturition ; the third in the micturition which can be experi-
mentally produced after cutting off all connections of the two
former with the bladder.
With what part of the cerebrum do we act in voluntary
retention of urine, when the tone of the vesical sphincter is
increased, and in micturition, when that muscle is voluntarily
relaxed ? To this we are unable to give any adequate reply.
We only know from Budge's early work that it is possible by
electrical stimulation of the cord to follow the spinal paths from
the bladder to the brain, as far as the cerebral peduncles.
We also know from the early work of Valentin that excitation
of different parts of the brain, especially of the cerebral
peduncles, the corpora striata, and the optic thalami, provoke
movements of the bladder. Certain experiments of Mosso and
Pellacani indicate that the cerebro-vesical paths run in the
posterior segment of the cord. Lastly we know from Bechterew
and Mislawski that electrical excitation of the sygmoid gyrus of
the cerebral cortex of dogs, behind the external extremity of the
sulcus cruciatus, produces contraction of the detrusor vesicae.
Sherrington also found a cortical centre for the bladder in
monkeys.
In man, according to the observations of Friedmann (1904),
who saw in a child that a circumscribed cortical lesion produced
an almost isolated disorder of the voluntary innervation of the
bladder, the cortical centre for the latter lies at the limit of the
upper third of the posterior central convolution, in the direct
contiguity of the upper parietal lobe. The centre for the arm is
located immediately in front of it. The same conclusion appears
also from the work of Czyhlarz and Marburg.
As regards the localisation of the spinal centres for the bladder,
Budge (1858) discovered in the spinal cord of rabbits a spot a few
millimetres in extent, which he termed the genito-spinal centre ;
this controls the contractions of the bladder, lowest part of the
intestine, and the vasa deferentia. In dogs, on the contrary,
Giannuzzi (1863) found two points in the lumbar cord which, if
mechanically excited by a deep puncture, react by contractions of
the bladder ; the first point corresponds with the level of the third,
the second with that of the fifth lumbar vertebra. There is no
doubt that the lumbar - sacral cord contains all the central
mechanisms both for the periodic emission and the retention of
urine. This is proved by the experiments of Goltz (1874) on dogs
whose cord was divided between the last dorsal and the first
viii THE EXCRETION OF UEINE 475
lumbar vertebrae. The immediate effect of this operation is
paralysis of the bladder, which, however, ceases in a few days,
while the operative sequelae disappear, and purely reflex micturi-
tion takes place, owing to the tension of the bladder which acts on
the centripetal nerves. Micturition can also be caused by holding
the animal in a vertical posture, and exciting the skin of the
perineum with slight mechanical stimuli.
Even when the spinal centres are occluded, the paralysis of the
bladder, although it lasts longer, gradually dies out, until the
normal function of the bladder is completely re-established. This
appears from the marvellous results obtained by Goltz and Ewald
(1896) on dogs deprived of the lumbo-sacral cord, which long
survived this serious operation. The bladder was much distended
at first by accumulation of urine, and had to be emptied artificially
by pressure on the peritoneal walls ; but the paralysis of the
detrusor slowly disappeared, until a few months after the operation
it was found that the bladder emptied itself periodically without
adventitious aid. The animal passed long periods without urinat-
ing, during which time the urine accumulated, and was evacuated
when the stimulus to the bladder walls became sufficient to induce
reflex micturition.
A very simple proof of this fact, showing that the bladder is
able to function normally without the help of the cerebrospinal
centres, by co-ordinated reflexes from the intravesicular ganglion
plexus, was obtained by von Zeissl (1896). He divided on a dog all
the nerves that run to the bladder, and found that after this
operation (which is much simpler than that of Goltz and Ewald)
the animal was able both to retain the urine and to expel it
periodically in a normal manner.
That in this case also the intravesicular ganglia function as
reflex centres appears very probable from the experimental demon-
stration of Sokowin, Nussbaum, Nawrocki and Skabitschewsky,
which show that the inferior mesenteric ganglion is capable of
functioning as a reflex centre for the bladder.
But the reflex action of the ganglion plexus of the bladder does
not cut out the rhythmical automatic activity of its own muscle
cells, independent of the ganglia. Rhythmic contractions are seen
in fact in the frog's bladder when it is excised from the animal,
as also in fragments of bladder which are subsequently found under
the microscope to show a total absence of ganglion cells (Pfalz).
The question has been much discussed as to whether the
mucous membrane of the bladder has any capacity for absorption,
and whether the urine accumulated in the bladder becomes
concentrated from absorption of water or any of the soluble
substances. The capacity of the bladder for absorption is readily
shown by the injection into it of toxic substances ; these take
effect after a certain time. The fact that the urine collected
476 PHYSIOLOGY CHAP.
during sleep is more concentrated than that of waking (Posner)
seems to indicate that the bladder does absorb some of the water
of the urine and concentrates it. But according to Kaupp, who
examined the composition of the urine in the bladder at different
times with a constant diet, no absorption of water takes place, but
only of urea, with excretion of sodium chloride. According to
Wundt, the concentration which the urine undergoes in the
bladder is greatest when the loss from the skin in the form of
sweat is also maximal.
Gerota (1897) showed by his accurate work on absorption in
the bladder that the mucous membrane of the bladder, unlike
that of the urethra, contains no lymphatics, which, on the contrary,
are plentiful in the muscular coat, .and probably communicate
with the lymph sinuses of the rnucosa. On injecting various
substances by puncture into the bladder, he arrived at the follow-
ing results : —
(a) The permeability of the mucous membrane of the bladder
is low owing to the multiple layers of the epithelium.
(6) Substances which have large molecules, such as the
alkaloids, do not diffuse : those with small molecules diffuse, but
very slowly and in very concentrated solutions.
(c) The diffusion of urea is too small to have any practical
importance.
The later work of 0. Cohnheim (1901), who, after tying the
ureters, introduced into the bladder different solutions, the con-
centration of which was determined before and after the experi-
ment, shows, in accordance with the previous conclusions of
Lusini, Boyer and Guinard, Pousson and Ligalas, that the normal
bladder has no capacity of absorption. The walls of the bladder
are impermeable both to salts and pigments and to water. The
fluids introduced are preserved as unaltered as if they were in a
glass vessel. It is only when the walls are necrosed or profoundly
injured by the action of caustic or toxic substances (e.g. sodium
fluoride) that they become permeable and assume the character of
an ordinary diffusion membrane.
Similar work, but with somewhat different results, was under-
taken by Galeotti and Fasola (1903). After previous ligation of
the ureters, they injected various solutions of sodium chloride or
saccharose into the bladder, which were hypo-, iso-, or hypertonic
to the blood, and of which the quantity and concentration were
exactly determined before and after the experiment. They made
two sets of experiments, one series being on the normal bladder,
the other on the bladder of which the walls were altered by
chloroform. The following were their results : —
(a) The epithelium of the bladder injured by chloroform
behaves like a ^semi-permeable membrane, through which osmotic
equilibrium is immediately established, with increase of volume if
viii THE EXCBETION OF UEINE 477
the fluid was hypotonic. (&) Normal epithelium, on the other
hand, does not as a rule set up osmotic equilibrium, but reacts
differently according to the requirements of the organism, (c)
With hypotonic solutions there is no change in quantity or con-
centration, (d} The same holds good for isotonic solutions if the
animal had been well supplied with food and drink, but if it
were suffering from hunger or thirst, partial absorption followed.
(e) With hypertonic solutions there was a marked absorption of
salt.
Both the reabsorption of water in case of need, and that of the
salt from hypertonic solutions (the excessive elimination of which
in a too-concentrated urine would under normal conditions involve
too great a loss of this useful substance), must, according to these
authors, be interpreted as useful reactions in the animal economy,
requirements to which the variable capacities of the epithelial cells
of the bladder can adapt themselves.
BIBLIOGRAPHY
For Physiology of Urinary Secretion :—
W. BOWMAN. Phil. Trans. London, 1842.
F. BIDDER. Archiv f. Anat. und Phys., 1844.
C. LUDWIG. Wagner's Handworterb. ii., 1844. Lehrbuch der Physiol. ii., 1856.
F. GOLL. Zeitschr. f. rat. Med., N.F., iv., 1854.
M. HERRMANN. Sitzsber. d. Wiener Akad. xxxvi., 1859.
OVERBECK. Ibidem, xlvii., 1863.
ECKHARD. Beitr. zur Anat. und Physiol. vii., 1869 ; v., 1870 ; vi., 1872.
C. USTIMOWITSCH. Ber. d. sachs. Ges. d. Wiss., 1870.
P. GRUTZNER. Archiv f. d. ges. Phys. xi., 1875.
NUSSBAUM. Pfliiger's Archiv, xvii., 1878.
A. MURRI. Rivista ciinica di Bologna, 1879.
R. HEIDENHAIN. Breslauer artzliche Zeitschr., 1879. Hermann's Handbuch fur
Phys. v., i. T., 1883.
RIBBERT. Virchow's Archiv, xciii., 1883.
ROY and COHNHEIM. Ibidem, xcii., 1883.
ADAMI. Journal of Physiol. vi., 1885.
DRESER. Zeitschr. f. Biologic, xxi., 1885. Archiv fiir exper. Pathol. und
Pharm. xxix., 1892.
J. MUNK. Virchow's Archiv, cvii., 1886.
J. MUNK and SENATOR. Ibidem, cxiv., 1888.
ALBERTONI and PISENTI. Archiv f. exp. Path, und Pharm. xxiii., 1887.
LIMBECK. Ibidem, xxv., 1889.
BRADFORD. Journal of Physiol. x., 1889. Proc. Soc. Roy. London, Ii., 1892.
ADOLPH SCHMIDT. Pfliiger's Archiv, xlviii., 1890.
F. SPALLITTA. La Sicilia medica, iii., 1891.
BERKLEY. Journal Path, and Bacteriol. i., 1893.
THOMPSON. Du Bois-Reymond's Archiv, 1894.
V. SOBIERANSKI. Archiv f. exp. Path, und Pharm. xxxv., 1895.
A. WALRAVENS. Arch. ital. de biologie, xxv., 1896.
T. D'EVANT. R. Ace. med. chir. di Napoli, 1889.
R. and A. MONTI. Verhandl. d. anat. Gesell. auf d. vierzenten Versamm. in
Pa via, 1900.
LINDEMANN. Zeitschr. f. Biol. xlii., 1901.
G. VINCI. Sul meccanismo di azione dei diuretici. Messina, 1902.
GURWITSCH. Pfliiger's Archiv, xci., 1902.
PHYSIOLOGY CHAP.
G. GALEOTTI. Arch. f. (Anat. u.) Physiol., 1902.
F. BOTTAZZI and R. ONORATO. Archivio d. Fisiol. i., 1904.
T. SCHILLING. Archiv f. exp. Path. u. Pharm., 1904.
R. HOBER and KONIGSBERG. Pfliiger's Archiv, cviii.
K. SPIRO and H. VOGT. Ergebn. d. Physiol. i. Part i., 1902.
L. v. RHORER. Pfliiger's Archiv, cix., 1905.
G. GALEOTTI. Zentralbl. f. Physiol. xxi., 1907.
For the Function of the Ureters copious references are given in : —
S. A. PROTOPOPOW. Pfliiger's Archiv, Ixvi., 1897.
Among the recent publications see : —
L. STERN. C. R. d. 1. Soc. d. Biol., 1903.
For the Function of the Bladder the following are the most important
publications : —
KOHLRAUSCH. Zur Phys. und Anat. der Beckenorgane. Leipzig, 1854.
HEIDENHAIN and COLBERG. Miiller's Archiv, 1858.
GIANNUZZI. Journal de la phys., 1863.
BUDGE. Zeitschr. fiir rat. Med., 1864. Pfliiger's Archiv, 1869-72. Virchow's
Archiv, xv., 1864.
OEHL. Journal de la phys., 1865-69.
BERT. Arch, de phys., 1869.
GOLTZ. Pfliiger's Archiv, 1874.
SOKOWIN. Ibidem, 1874.
NUSSBAUM. Nawrocki's Arbeiten. Warschau, 1879.
Mosso and PELLACANI. R. Ace. dei Lincei, 1882.
NAWROCKI and SKABITSCHEWSKY. Pfliiger's Archiv, 1891.
v. ZEISSL. Ibidem, 1893-94. Wiener klin. Wochenschr., 1894.
LANGLEY and ANDERSON. Journal of Phys., 1896.
GOLTZ and EWALD. Pfliiger's Archiv, 1896.
REHFISCH. Virchow's Archiv, 1897.
GEROTA. Du Bois-Reymoud's. Archiv, 1897.
HANC. Pfliiger's Archiv, Ixxiii., 1898.
GRIFFITHS. Journal of Anat. and Phys., xxv., 1894.
VERSARI. Ricerche dellaboratorio di anatomia di Roma, ecc. vi., 1897.
0. COHNHEIM. Zeitschr. f. Biol. xli., 1901.
G. FASOLA and G. GALEOTTI. Journ. d. Physiol. et d. Pathol. gener. v., 1903,
also Archives ital. d. biol. xxix., 1903.
Recent English Literature : —
C. C. STEWART. The Relaxation of the Bladder Muscles of the Cat. Amer.
Journ. of Physiol., 1900, iii. 1.
D. H. DE SOUZA. On the Effects of Venous Obstruction on the Secretion of Urine.
Journ. of Physiol., 1900-1, xxvi. 139.
A. R. CUSHNY. On Diuresis and the Permeability of the Renal Cells. Journ. of
Physiol., 1901-2, xxvii. 429.
F. D. BOYD. Some Experiments on the Functions of the Medulla of the Kidney.
Journ. of Physiol., 1902, xxviii. 76.
A. R. CUSHNY. On Saline Diuresis. Journ. of Physiol., 1902, xxviii. 431.
C. H. FAGGE. On the Innervation of the Urinary Passages in the Dog. Journ. of
Physiol., 1902, xxviii. 304.
T. SOLLMANN. The Mechanism of the Retention of Chlorides : a Contribution to
the Theory of Urine Secretion. Amer. Journ. of Physiol., 1903, viii. 155.
T. SOLLMANN. The Effect of Diuretics, Nephritic Poisons, and other Agencies on
the Chlorides of the Urine. Amer. Journ. of Physiol., 1903, ix. 425.
T. SOLLMANN. The Comparative Diuretic Effect of Saline Solutions. Amer. Journ.
of Physiol., 1903, x. 454.
H. D. HASKINS. The Effect of Diuretics on the Urine with a diet poor in Salts.
Amer. Journ. of Physiol., 1904, x. 362.
0. H. BROWN. Effects of Certain Salts on Kidney Excretion, with Special Refer-
ence to Glycosuria. Amer. Journ. of Physiol., 1904, x. 378.
viii THE EXCRETION OF URINE 479
A. R. CUSHNY. On the Secretion of Acid by the Kidney. Journ. of Physiol. ,
1904, xxxi. 188.
T. SOLLMANN. Perfusion Experiments on Excised Kidneys. Amer. Journ. of
Physiol., 1905, xiii. 241.
J. BARCROFT and T. G. BRODIE. The Gaseous Metabolism of the Kidney. Journ.
of Physiol., 1905, xxxii. 18.
F. P. UNDERBILL and 0. E. CLOSSON. The Mechanism of Salt Glycosuria. Amer.
Journ. of Physiol., 1905-6, xv. 321.
J. BARCROFT and T. G. BRODIE. The Gaseous Metabolism of the Kidney. Journ.
of Physiol., 1905-6, xxxiii. 52.
D. R. LUCAS. Studies of the Peristalsis of the Ureter of Dogs by the Graphic
Method. Amer. Journ. of Physiol., 1906-7, xvii. 392.
T. G. BRODIE and W. C. CULLIS. On the Secretion of Urine. Journ. of Physiol. ,
1906, xxxiv. 224.
W. C. CULLIS. On Secretion in the Frog's Kidney. Journ. of Physiol., 1906,
xxxiv. 250.
T. SOLLMANX. Perfusion Experiments on Excised Kidneys. VII. Solutions of
Electrolytes. Amer. Journ. of .Physiol., 1907, xix. 233.
W. W. WILLIAMS. Perfusion Experiments on Excised Kidneys. VIII. The
Effects of Solutions on the Histological Appearance of Kidney Sections.
Amer. Journ. of Physiol., 1907, xix. 252.
T. R. ELLIOT. The Innervation of the Bladder and Urethra. Journ. of Physiol. ,
1906-7, xxxv. 367.
F. A. BAINBRIDGE and A. P. BEDDARD. The Relation of the Kidneys to Metabolism.
(Prelimin. communic. ) Proc. Roy. Soc. of London, 1907, Ixxix. B, 75.
T. SOLLMANN and R. A. HATCHER. Perfusion Experiments on Excised Kidneys.
IX. The Effects of Various Poisons. Amer. Journ. of Physiol., 1908,
xxi. 37.
D. R. LUCAS. Physiological and Pharmacological Studies of the Ureter. Amer.
Journ. of Physiol., 1908, xxii. 245.
G. D. SHAFER. Kidney Secretion of Indigo Carmine, Methylene, Blue and
Sodium Carminate. Amer. Journ. of Physiol., 1908, xxii. 335.
W. C. CULLIS. Further Experiments upon the Secretion of Urine in the Frog.
Proc. of the Physiol. Soc., 1908. Journ. of Physiol., xxxvii. p. xvi.
D. R. HOOKER. A Study of the Isolated Kidney. The Influence .of Pulse
Pressure upon Renal Function. Amer. Journ. of Physiol., 1910-11, xxvii. 24.
TH. B. BARRINGER and B. S. BARRINGER. A Comparison of the Total Nitrogen
Excretion of Either Kidney in Normal Individuals during varying Periods of
Time. Amer. Journ. of Physiol., 1910-11, xxvii. 119.
J. BARCROFT and H. STRAUB. The Secretion of Urine. Journ. of Physiol.,
1910-11, xli. 145.
CHAPTEE IX
THE SKIN AND CUTANEOUS GLANDS
CONTENTS. — 1. Structure of the skin and continuous desquamation of the
stratum corneum. 2. Coiled sweat glands and sensible and insensible cutaneous
secretion. 3. Chemical substances excreted in perspiration. 4. Innervation of sweat
glands. 5. Sebaceous glands and specilic formation of sebum. 6. Mammary
glands. 7. Chemical composition of milk. 8. Influence of diet on the secretion
of milk. Origin of secretory products. 9. Histological and chemical processes of
milk formation. 10. Influence of nervous system on the milk secretion. 11.
Absorption by the skin. Bibliography.
THE body suffers considerable loss of material by the skin, as well
as from the lungs, intestine, and kidneys. But this loss consists
only to a minimal extent in katabolic products. As an excretory
organ and blood purifier, the skin (by the glandular secretions
which it pours out) is therefore of secondary importance. Its
functions as a protective organ are far more significant. It not
only regulates the internal heat and adapts it to the external
environment, lubricates the stratum corneum of the epidermis and
the hair, and renders them elastic, but it further provides the
fittest nutriment for the new-born animal, which is the most
fundamental form of protection of the species.
In this chapter we shall deal with the skin, not as the seat of
the sense-organs (which will be fully discussed in Vol. IV.), but only
as an external integument, provided with innumerable glands by
which the body suffers loss, either in the form of gas and vapour
(perspiration), of water (sweat), of adipose and horny substances
(sebaceous and ceruminous secretions, epidermoid desquamation),
or of an alimentary fluid (milk secretion). Each of these products
has a distinct physiological significance and special character
which it must be our task to determine. Lastly, we shall discuss
the question whether, and how far, the skin may be regarded as
an absorbing surface.
I. Without entering into details of the minute structure
of the skin, the interest of which is mainly morphological, we
shall confine ourselves to stating that two principal layers can be
distinguished, the epidermis (or cuticle), and the derma (cutis
480
CHAP, ix THE SKIN AND CUTANEOUS GLANDS 481
vera, or coriuui) ; the former corresponds with the epithelium, the
latter with the areolar substrate of the mucous membranes, which
are an invagination of the skin.
Both in the epidermis and in the derma several layers can be
distinguished : in the first, the harder, horny layer (stratum
corneum), and the softer, mucous or Malpighian layer (rete
mucosum) ; in the second, the corium proper, and the panniculus
adiposus (Fig. 129).
From the physiological point of view it is an important fact
that the many layers of cells which make up the epidermis, from
£ O
PIG. 129. — Vertical section of skin and subcutaneous tissue, from the end of the thumb, across the
ridges and furrows. (Kolliker.) 20 diameters, a, horny ; b, Malpighian layer of epidermis ;
c, corium ; d, panniculus adiposus ; e, papillae on the ridges ; /, fat clusters ; g, sweat glands ;
h, sweat ducts ; i, their openings on the surface.
the deepest stratum of the Malpighian layer (which fit into the
surface of the corium) to the most superficial of the horny layer,
undergo perpetual modifications in their form and physico-
chemical characters, corresponding with so many alternating
phases of their existence. The deepest layer is the youngest, and
consists of cells vertical to the surface of the corium, to which
they are attached by denticulations at their lower ends (Fig. 130).
The next and older layers consist of rounded or polyhedral cells,
and become more flattened as they approach the surface. All these
cells have fine intercellular processes or bridges, which, if viewed
separately, give an effect of spines (the so-called " spiny cells ").
VOL. II 2 I
482
PHYSIOLOGY
CHAP.
fc.1... ... — >„
FKI. 130. — Section of epidermis from skin of finger,
coloured by picro-carmine. (Ranvier.) a, stratum
corneum ; 6, stratum lucidum, with scales of eleidin ;
c, stratum granulosum full of eleidin granules ; d,
deep cells and intercellular canals of rete mucosum ;
e, dentations of deepest cells, for attachment to
cutis vera.
Between the connecting bridges there is a system of intercellular
channels (Bizzozero) which may become dilated with excess of
fluid, on which the bridges
between the cells are more
apparent. These spiny cells
contain pigment granules,
which are more abundant
in proportion as the skin is
darker. The colour of the
skin in the black races is
due to this pigment, which
is particularly plentiful in
the deeper cells of the Mal-
pighian layer (Fig. 131).
The more superficial cells
of this layer are spindle-
shaped, and contain a
number of granules of a
substance (eleidiu) that
stains deeply with carmine
(stratum granulosum of
Langerhans).
Between this and the
horny superficial stratum there is in some parts of the skin an
intermediate layer which looks clear,
and is formed of cells with indistinct
outlines ; this is probably a transition
between the cells of the granular and
those of the horny layers (stratum
lucidum of Oehl).
The cells of the stratum corneum,
which are nearly all destitute of a
nucleus, may be regarded as senile
cells, degenerated into horny sub-
stance, which, in proportion as they
approach the surface, lose all their
vital character and are finally reduced
to hard, dry, transparent scales,
perpetually cast off from the surface
of the skin by desquamation (scurf).
So that by this continual shedding
of the superficial lamellae, which
are replaced by those of the sub-
jacent layers, the body suffers a
constant loss of horny substance,
comparable with any other loss of substance by excretion.
The horny scales give no protein reaction, but contain
Fin. 131.— Skin of the ne^ro. Vt'Hirnl
section, 250 diameters. (Kiilliker.)
a, a, cutaneous papillae ; ?), undermost
and dark - coloured layer of viTtii-il
epidermis cells ; c, mucous or Malpi-
ghian layer ; d, horny layer.
ix THE SKIN AND CUTANEOUS GLANDS 483
derivative, belonging to the group of sclero- proteins, which is
known as keratin. The constitution of this is unknown ; it has
the same percentage composition as the proteins, but contains a
considerable amount of sulphur, partly in loose combination with
other elements, from which it separates on boiling in alkaline
solution.
It is difficult to estimate the amount of horny substance
detached from the surface of the body in the form of epidermoid
scales. According to Funke, the loss of lamellae in the sweat
amounts to 6 grms. in 24 hours. Moleschott (1878), on the
strength of a fact observed on himself (viz. that a scrap of
epidermis sloughed off in a boil was regenerated in 34 days),
calculated ingeniously that an individual of average body-weight
must lose 14'35 grms. epidermis daily, containing 12'20 grms.
horny substance, and 2-10 grms. nitrogen. These figures are
exaggerated and incredible, and are based on improbable hypotheses,
particularly on the assumption that the epidermis of any cutaneous
area (from which it has been removed) is regenerated in the same
time in which it is renewed by successive desquamations over the
whole remainder of the normal cutaneous surface.
Moleschott again (on the strength of data furnished him by
Berthold as to the growth of hairs in the beard, and those noted
by himself as to the growth of hair and nails, which are horny
tissues essentially analogous to the epidermis) computed the mean
daily product of these structures at 0'26 grms. i.e., far less than he
calculated for the epidermis alone. It is also remarkable that the
production of horny tissues is much diminished by age, that it is
greater in summer than in autumn, and is accelerated by frequent
removal. By leaving less time between one cutting of the hair
and the next, says Moleschott, the growth of the hair is accelerated.
To us, therefore, it appears logical to conclude that on removing
the skin from a cutaneous surface, e.g. by application of blisters,
it should be regenerated in a much shorter time than is required
for the complete renewal of the epidermis over the whole area of
the intact skin.
The regeneration of the stratum corneum is effected by mitotic
division of the cells in the Malpighian layer. The karyokinetic
figures are seen only in the spiny cells, not merely in the deepest
stratum contiguous to the papillae of the cerium, but in the less
profound strata as well. While these cells are multiplying, the
more superficial are changing into cells of the granular layer. It
is probable that the granules of these cells are those which form
the keratin, or become converted into it. The more superficial
cells of the stratum granulosum are simultaneously converted into
those of the stratum lucidum, and these lastly into the scales of.
the stratum corneum.
"We shall consider the structure of the corium, and more
484
PHYSIOLOGY
CHAP.
particularly of the papillary layer, when we come to study the
skin as the seat of the special senses. Here it is enough to say
that the depressions between the papillae are filled by cells of the
Malpighian layer, which is therefore thicker at these points. The
Fio. 132. — Compound papillae from the palm of the hand. (Kolliker.) 60 diameters, a, basis of a
papilla ; 6, 6, divisions or branches of the same ; c, c, branches belonging to papillae of which
the bases are hidden from view.
surface of the epidermis is also uneven, and presents prominences
and depressions at a number of places, corresponding with the
position of the papillae or interpapillary spaces. These prominences
are termed the papillary ridges of the epidermis.
In-many parts of the skin, particularly on the palmar surface
Fio. 133. — Linear sweat prints from palmar surface of finger (Aubert's photographic method). The
white line marks the papillary ridges, forming a vortex at the tip ; the black lines are the
furrows which lie between the crests.
of the hand and fingers, the papillae of the corium are compound,
i.e. cleft at the summit into two or more secondary points, which
are ranged in lines separated by superficial furrows (Fig. 132). The
surface of the cuticle which covers these papillae shows ridges
separated by characteristic curved lines, which form a sort of
vortex at the culminating point of the digit (Fig. 133). Under a
IX
THE SKIN AND CUTANEOUS GLANDS
485
high power, these ridges are divided not only by longitudinal
furrows, but also at short and fairly regular intervals by less
profound transverse furrows with a minute funnel-shaped orifice
in the middle of each, which is the mouth of a sweat-gland
(Fig. 134).
II. The Sudiferous or Sweat - Glands, already known to
Stensen, Malpighi, Boerhaave and others, and more exactly located
as regards their orifices by Eichhorn (1826), were first described
accurately and almost simultaneously by Purkinje, Wendt,
Breschet (1834), and Gurtl (1835), not only for man but also for
il
Pio. 134.— (Left) Four ridges of the epidermis, with short furrows across them, and the orifices
of the sudoriferous ducts. (Breschet.)
tuDe (commencing uuct; ; a, intertuouiar connective tissue wiui uiuuu-vcsscis. *
across the secreting tube, 1 is the basement membrane ; 2, the muscular fibres cut across ;
3, the secreting epithelium lining the tube.
the domestic animals. They consist of long tubes in which the
secreting part is coiled up into a ball, seated at varying depths of
the corium and in the first layers of the subcutaneous adipose
tissue (Fig. 129). The excretory duct or conducting tube is con-
tinued from the coiled gland through the corium, and in a spiral
course through the epidermis, opening between two adjacent
papillae with the widened orifice described above. The secreting
tube is considerably larger than the duct, and has a wider lumen
(Fig. 135). It has a basement membrane, plain muscular fibres,
and one or two layers of columnar cells characterised by a very
distinct cuticular lining. The excretory duct is covered with a
single layer of cells, which are smaller and have no true cuticle.
Although direct evidence is wanting, it is probable on analogy
486 PHYSIOLOGY CHAP."
that the secretion of these glands is principally, if not exclusively,
the work of the cells in the coiled glands. The muscle-cells which
surround the basement membrane, and are interposed between it
and the epithelium, apparently serve by their contraction to
accelerate the flow of the secretion along the duct.
Man has the capacity of sweating diffusely over the whole of
the surface of the skin, but perspires more easily and copiously
by the face, particularly the forehead, the palm of the hand, the
sole of the foot, the axilla, and the groins. The monkey sweats
more from the top of its nose, and very little from the palm of the
hand and sole of the foot, although these parts are hairless. The
horse and sheep sweat freely from all parts of the body, although
hairy ; the calf less readily ; the goat, rabbit, mouse, and rat not at
all. Carnivora, generally speaking, sweat only from the ball of
the foot, and even there the dog sweats little or not at all, while
the cat on the other hand (the chosen subject for physiological
investigation into sweat-secretion) perspires readily and copiously
in that part. The pig sweats almost incessantly at the flat
surface of the snout, where Gurtl found a large development of
sweat glands. In the ox the nasal pinnae (alae) are continually
moist with sweat.
The power of sweating mainly or exclusively from certain
definite areas of the skin is in proportion not so much with the
number of sudoriferous glands in those regions and their total
absence in others, as with the varying secretory activity of these
glands. In fact, the coiled form of gland is not inseparably
associated with the function of sweating. There are highly
developed coiled glands which never secrete sweat during the
whole life-time. Such, e.g., are the glands existing in animals that
never sweat from any part of the skin, or those in regions where
sweat is never secreted. Obviously, these glands must have
another function, distinct from that of sweat secretion. We shall
see in effect that they probably have the same function as the
sebaceous glands. The coiled glands which abound in the skin of
the external auditory nieatus are a typical example of glands
which, with the complete structure of sudoriferous glands, have no
other office than that of secreting the cerumen which covers and
protects this passage.
Krause (1844) made a laborious investigation of the dis-
tribution of the sweat glands in the different regions of the skin
in man, and determined the number that could be counted in
square inch of surface. On reducing the unit of measurement
square centimetres the results were approximately as follows : —
In the forehead . . . . .140
„ cheeks 60
„ chest, abdomen, forearm . . 225
„ neck, back, rump ... 50
ix THE SKIN AND CUTANEOUS GLANDS 487
In the upper arm and leg . . . 55-70
,, palm of hand .... 310
„ back of hand .... 170
„ sole of foot .... 300
„ dorsum of foot . ,. . 100
They are more numerous in the axilla than elsewhere, but hard to
count, because the excretory tubes of several glands converge into
one single excreting duct.
Aubert (Lyons) invented a very elegant method for the exact calculation
of the enormous number of sweat glands in the skin. A sheet of ordinary
white paper is closely applied to any area of perfectly dry skin surface, for a
period of 30-80 minutes. On then plunging it into a 0'25 per cent silver
nitrate solution, and exposing it to sunshine, the ground of the paper turns
black, but every point at which it came in contact with the mouth of a sweat
gland remains white, so that a photograph is obtained in which the orifices
of the glands appear as ducts (Fig. 136). The explanation is very simple.
Sweat is continually given off from the mouths of the sudoriferous glands in
the form of invisible perspiration. The sweat contains chlorides which are
deposited on the paper only at the points corresponding with the glandular
orifices, so that these points only react to the silver nitrate by forming silver
chloride. If the paper is applied, on the contrary, to a surface that is visibly
perspiring, the sweat with its chlorides will cover the whole surface of the
papillary ridges, and instead of dots, an exact impression of the outline of the
ridges is seen as a white line, the furrows that bound them coming out
black (Fig. 133).
So long as the secretion of sweat from the coiled glands is
below a certain narrow limit, the water excreted (with the volatile
substances of the sweat) evaporates from the surface of the skin,
which remains dry (perspiratio insensibilis) ; but when the
secretion increases, or evaporation is hindered by the state of the
atmosphere, sweat appears on the surface of the skin. First
minute droplets form at the orifices of the coiled glands, next
these run together and form larger drops, finally by gravity they
flow over the skin, or saturate the clothing (perspiratio sensibilis).
The loss of substance, particularly of water, from the human
body by the skin is undoubtedly enormous, but it varies consider-
ably with different circumstances. The first experimental attempts
to determine this loss were made by Santorio (1614). He weighed
the intake of food and drink, as well as the ponderable excreta of
his own body, and found (after remaining whole days on the
balance) that f of the weight of the ingesta are eliminated by
the skin and lungs. Dodart (1725) made similar experiments.
The question was subsequently taken up by Lavoisier and Seguin
(1790), who estimated the water excreted from the human skin at
one litre in 24 hours. In his later work on the total excretion by
the skin and lungs, W. F. Edwards (1824) found that it varied
quantitatively in different animals in ratio with their weight.
But he erred in differentiating between sudoratio and perspiratio,
as if there were two different secretions, instead of two different
488
PHYSIOLOGY
CHAP.
phases of a single secretory process. It cannot be absolutely denied
that a minimal degree of aqueous evaporation may take place over
the entire surface of the skin independent of any process of secre-
tion, but there can be no doubt that almost the whole of the
insensible loss of water suffered by the skin is due to the secretion
of sweat, which evaporates as fast as it creeps from the orifices of
the glands. Evidence for this has recently been given by Aubert
in his photographs of the sweat-drops during insensible perspiration
(Fig. 136).
It is also important to note from recent work on general
metabolism (that of Pettenkofer and Voit in particular) on
calculating the average results obtained by the evaporation of
PIG. 136.— Sweat prints from back of hand. (Aubert.) The pores or mouths of the sweat
glands are shown as white dots on a black ground.
water in cutaneous and pulmonary respiration jointly, as compared
with the water eliminated in the urine, that
the dog excretes 70 % H.,O in the urine, 30 % in cutaneous secretion.
„ man „ 60% „ 40%
„ horse „ 30 % „ 70 %
In carnivora, therefore, the loss of water by the kidneys
greatly exceeds that by sweating; in herbivora, the contrary is
the case ; in man, excretion by the kidneys is slightly in excess of
that by the sudoriferous glands, approximating to the carnivora
rather than to the herbivora. The daily loss of water by the
skin amounts in man on an average to 6| the body- weight, and
is almost double that by pulmonary excretion.
As every one knows, there is a marked antagonism between
the loss of water by the kidneys and intestines, and that given off
ix THE SKIN AND CUTANEOUS GLANDS 489
by the skin and lungs. On perspiring freely, as in summer,
micturition is scanty; in winter, on the contrary, when visible
perspiration is suspended, micturition is frequent and copious.
But apart from the influence of season and temperature in general,
clinical observation shows that in all cases in which there is
excessive loss by the kidneys and intestines (diabetes, diarrhoea)
this is compensated by a marked dry ness of the skin ; with the
opposite conditions the contrary is observed (nephritis, anuria).
A good many fallacies prevail as to the intensity of cutaneous
perspiration. It is often stated, e.g., that not only the temperature,
but also the humidity of the surrounding atmosphere, increase
cutaneous secretion, whereas in reality the latter reduces evapora-
tion, or insensible perspiration, by increasing sweat, or sensible
perspiration. Frequent renewal of the air in contact with the
skin acts in the opposite sense : natural or artificial ventilation of
the atmosphere, within certain limits, does not perceptibly diminish
the cutaneous secretion, but it reduces sensible perspiration by
increasing evaporation.
There is no constant relation between height of external
temperature and intensity of cutaneous secretion, the capacity
for sweating being very different for different individuals of the
same species. Caeteris paribus, however, perspiration in one and
the same individual increases in proportion with the external
temperature. In order to rouse the skin to a more active secretion
of sweat the external temperature must approximate to 33° C.
(Schierbeck, 1893).
Besides external conditions, cutaneous secretion may be con-
siderably affected by alterations in the internal conditions, among
which are : — (a) amount and quality of the food ingested, and
particularly what is drunk; (&) muscular activity or rest, which
respectively increase or diminish cardio-vascular activity ; (c) use
of certain drugs known as diaphoretics, e.g. pilocarpine, muscarine,
partially also nicotine and physostigmine (or the drugs which
have an opposite, antidiaphoretic action, e.g. atropine and daturine) ;
(d) sudden or violent mental emotions (anguish, anger, joy) which
increase the cutaneous secretion, independently of dilatation of
the cutaneous vessels (blushing), or their contraction (pallor).
III. Since the external or internal conditions that promote or
hinder sweat secretion are so variable, it is easy to see why the
data collected by 'different observers as to the amount of sweat
secreted in the time-unit are of little general value.
When collected in large quantities for purposes of analysis, the
sweat is a slightly turbid, almost colourless fluid, salt in taste, with
a more or less powerful rancid smell, due to the volatile fatty acids.
In some regions, e.g. the axilla, groins, and pubis, the sweat
has a more penetrating odour, which may be highly unpleasant,
and is due to the special fatty acids mingled with the secretion.
490 PHYSIOLOGY CHAP.
When examined under the microscope, the sweat shows a
number of epidermoid scales detached from the surface of the
skin, as well as fat-granules.
Human sweat gives an acid reaction under ordinary conditions ;
in the horse and cat it is almost always alkaline (Luchsinger).
The acidity of human sweat is due to the fatty acids. Some
authors hold that this depends on the admixture of the secretion
from the sebaceous glands, and state that in parts where the
latter are absent, e.g. the palm of the hand after well washing,
the sweat has an alkaline reaction (Tourton) ; others again
contradict this observation (Franc,ois-Franck, Albini). Since we
know (supra) that many coiled glands have throughout life a
function that differs in no way from that of the sebaceous glands,
it seems logical to assume that the coiled glands which do serve
the sudorific function also secrete along with the sweat a small
amount of sebum, which (infra) is rich in fatty substances of
various kinds, and gives to the whole secretion its acid reaction.
Trlimpy and Luchsinger (1878) established the important fact
that during profuse sweating the acidity of human sweat gradually
diminishes till it becomes neutral, and is eventually alkaline like
that of the horse. This phenomenon is easily explained on the
assumption that the acid sebum of the secretion, which is a slowly
formed product of the secretory cells, is easily exhausted, while
the watery sweat, which has the alkaline reaction of the blood
and lymph from which it is derived, persists.
Various methods have been tried for collecting the products of cutaneous
secretion from the whole surface of the body or from any part of it. If the
forearm is enclosed in a rubber bag, with a glass bottle at one end, evapora-
tion from the skin is checked, and the whole of the exudate runs into the
bottle in the form of sweat (Anselniino, 1844). The subject may be enclosed
in a Pettenkofer and Yoit's respiration chamber, breathing through a rubber
mask applied to the month and nostrils, with tubes attached. Comparison
of the water and carbon dioxide of the air that enters and leaves the
chamber gives the sum of the products evaporated from the entire
cutaneous surface (Schierbeck, 1893). If the subject is enclosed in a
receptacle (with the exception of the head), and the temperature of the
surrounding air is raised, a copious secretion of sweat is induced from the
whole cutaneous surface, and collects at the bottom of the receiver (Favre,
1852). By the simpler method of the so-called vapour -bath, which is
produced by raising the temperature of the surrounding atmosphere, it is
possible to collect the greater part of the sweat that runs off the skin, so as to
determine its content of organic substances (Argutinsky, 1890).
Quantitative analyses of the principal organic and mineral
constituents of the sweat led to widely dissimilar results, according
to Schottin (1851), Favre (1852), Funke (1858). All the analyses,
however, point to the fact that sweat is the most watery of all
the secretions, since it contains not more than 0'5-1'5 per cent
solids, of which about | consists of mineral substances, mainly
sodium chloride. The following table, drawn up by Harnack, gives
ix THE SKIN AND CUTANEOUS GLANDS 491
the composition of the sweat in a patient suffering from rheumatism,
who was made to sweat 1-2 hours in a bath : —
Specific gravity .... 1003-1006
Water 99'09-99'lG per cent.
Solids 0-91- 0-85
Organic substances . . . 0'42- 0'85
Inorganic substances . . . 0'67- 0'65
Sodium chloride . . , . 0'52
Earthy phosphates . . 0-03
Sulphuric acid .... 0 05
Potassium 0'04
Urea 0'12
This table does not include either the lactic acid or the
sudoric or hidrotic acid (a nitrogenous acid with the empirical
formula C10H16N2013) of Favre, which were not found by any
other observers.
The chlorides, and still more the phosphates and sulphates
of sweat, are less abundant than those of urine, as shown by
Kast (1887).
There is now no doubt as to the presence of urea in normal
sweat. The different amounts found by different observers may
partly depend on the dissimilar interval between the secretion
and its analysis, in which a certain variable proportion of the
urea undergoes conversion by arnmoniacal fermentation.
According to Argutinsky's experiments on himself, by the
vapour-bath, as to the total nitrogen eliminated from the skin,
G8'5-74'9 per cent is present in the sweat in the form of urea,
and 31'5-25'1 per cent in the form of ammonia. The same
observer estimated the amount of nitrogen eliminated in the
sweat during severe walking or climbing exercise. With this
object he wore a special suit of cotton clothes, which were
extracted, when saturated with sweat, at the end of the excursion,
the extract being analysed by Kjeldahl's method. The following
were the results of three experiments : —
Excursion of about 20-22 kilos, in 7 hrs. (July). N excretion = 704 '4 mgrins.
„ 18-20 „ partly climbing (Aug.) „ =753'5 „
18-20 „ „ (Oct.) „ =219-3 „
According to Argutinsky the nitrogen excreted by the skin
may amount to 4'7 per cent of that eliminated by the urine, which
should be taken into account in making exact calculations of the
total products of metabolism.
Besides urea and ammonia, other urinary constituents have
been found in human sweat. Capranica detected creatinine
in the proportion of '04 per cent. In uraemic conditions the
cutaneous excretion of these products may be enormously increased.
Schottin and others found urea crystals in the skin of uraemics.
The small quantity of fatty acids which causes the character-
492
PHYSIOLOGY
CHAP.
istic odour of sweat are made up of formic, acetic, butyric,
propionic, and -capronic acid. Ethereal sulphates of phenol and
scatole are also present, but only in small amounts (Kast). The
perspiration from the armpit sometimes stains the underclothing
blue, from the indican present in the sweat. It is, however,
doubtful whether this indican conies from indoxyl secreted in the
sweat, or from indoxyl developed by chromogenic bacteria.
Lastly, human sweat nearly always contains a small amount
of protein (0'045 per cent, which is a normal constituent in the
sweat of horses, and causes the characteristic foam of their
perspiration), as well as two enzymes, one diastatic or saccharify-
ing, the other tryptic or proteoclastic.
Eeference should be made, in reviewing the more recent
work on the chemical constitution of the .sweat, to the researches
of W. Camerer, jun. (1901), who collected the perspiration from
healthy subjects in light-, hot-air, or vapour-baths, and analysed it
accurately with the following results : —
TABLE I.
100 c.c. Sweat contain
Water.
Dry
Residue.
Ethereal
Extract.
Total
Nitrogen.
Urea
Nitrogen.
Ammonia
Nitrogen.
Ash.
NaCl.
rroteins.
1. Light-Bath .
97-9
2-1
0-17
0-188
—
—
1-040
—
—
2. Light-Bath .
—
—
—
0-150
0-051
0-012
0-866
0-66
Trace
3. Hot-air Bath
98-3
1-7
0-02
0-137
—
0-011
1-042
0-78
—
4. Vapour-Bath
99-24
0-76
0-085
0-091
0-031
0-006
0-465
0-34
Trace
TABLE TI.
100 Parts Dry Residue
contain
100 Parts Total Nitrogen
contain
100 Parts
Ash contain
Ethereal
Extract.
Total
Nitrogen.
Ash.
Urea
Nitrogen.
Ammonia
Nitrogen.
Ash.
1. Light-Bath. .
8-4
9-3
57-2
—
—
55-3
—
2. Light-Bath. .
—
—
—
34
8-0
57-7
76
3. Hot-air Bath .
11-8
8-1
61-3
—
8-0
75-3
75
4. Vapour-Bath .
Average
11-2
12-0
61-2
34
6-6
51-1
73
10-5
9'8
57-9
34
7-5
59-8
75
ix THE SKIN AND CUTANEOUS GLANDS 493
The much lower concentration of the sweat obtained by vapour
baths is evidently due to its dilution by the water condensed
from the steam.
There is a marked difference between these results and those
obtained by Argutinsky, since 34 per cent of the total nitrogen
consists of urea-nitrogen and 7'5 of ammonia-nitrogen. The rest
is accounted for by traces of protein and other nitrogenous
substances, including uric acid, which was demonstrated by the
murexide test in experiments 1, 2, 4 of the table.
Just as the nature of the solid substances eliminated by the
sudoriferous glands in the form of sweat shows the function of the
skin to be subsidiary to, and in a certain measure vicarious of, that
of the kidneys, so the insensible output of water and carbonic acid
with simultaneous absorption of oxygen, indicates that the skin
is a respiratory surface, aiding and partly supplementing the
function of the lungs. In man and mammals, however, the
gaseous exchanges by the skin are insignificant in comparison with
those of the lungs. According to Aubert and Lange, the total
excretion of carbonic acid by the human skin is only 3-4 grms.
per diem, but this figure was doubled in the later work of
Schierbeck.
The small amount of C02 given off by the skin is not, as some
hold, due to the thickness of the epidermis. In all probability
there is no sensible respiratory gas exchange through the stratum
corneum, but this, like the excretion of water, is entirely accom-
plished by the ducts of the cutaneous glands. The scanty
secretion of C02 is more likely due to the fact that the skin is
irrigated by arterial blood, in which the carbonic acid is at low
tension. In certain amphibia, on the contrary, e.g. frogs, the
gaseous exchange that takes place by the skin is (in consequence
of the limited pulmonary surface, the habitual moisture of the
skin, and above all the fact that, like the lungs, it is supplied with
mixed blood from the single ventricle of the heart) in excess of
that by the lungs, so that these animals live for a long time after
the lungs have been cut out.
In man it is doubtful whether the excretion of carbonic acid
by the skin and the (usually smaller) absorption of oxygen occur,
as in the lungs, principally by a process of diffusion. The former
(as was rightly observed by Foster) might not be derived directly
from the blood, but from decomposition of the carbonates con-
tained in the sweat ; in the same way the oxygen that disappears
may not be absorbed by the blood circulating in the skin, but may
be utilised to oxidise some of the organic constituents of the sweat.
From this point of view the results of Schierbeck's experiments
(1893) are interesting. He studied the effect on human cutaneous
secretion of different degrees of external temperature, varying from
29° to 39° C., and found that the excretion of C02 does not vary
494 PHYSIOLOGY CHAP.
perceptibly until the external temperature rises from 29° to 33° C.
Between these -limits no formation of sweat drops on the skin is
apparent, perspiration maintains its insensible character, and not
more than 35 c.c. carbonic acid are given off per hour ( = 9 grrns.
per diem). When, on the contrary, the external temperature rises
above 33 and reaches 39° C. there is a rapid and progressive
increase in C02 excretion by the skin. Above 33° perspiration
suddenly becomes sensible, i.e. it assumes the form of sweat, and
simultaneously with this the amount of C02 excreted is suddenly
doubled, and increases with the further increase of temperature
and secretion of sweat (0'87-1'23 grms. per hour= 20-9-29'5 grms.
in 24 hours). These results of Schierbeck indicate that the
amount of carbonic acid given off by the skin depends not upon
the quantity of blood circulating in it, but rather upon the
secretory work of the cutaneous glands ; this rises abruptly at the
critical temperature of 33° C. to an output of twice the amount
of carbonic acid, which thus comes not from the blood directly,
but from the sudoriferous glands of which it is a secretion
product.
W. Barratt (1897-99) made a careful study of cutaneous
secretion in man under different experimental conditions, by the
following method. As in the plethysmograph, the arm was
introduced into a metal cylinder made impervious by a rubber
sleeve through which air, free from carbonic acid and aqueous
vapour, was circulated, and subsequently passed into vessels con-
taining sulphuric acid and caustic soda. The metal cylinder was
surrounded by a water-bath, which could be heated to various
temperatures. Experiments on the normal arm showed that the
elimination of carbonic acid is very small in comparison with that
of water. The former at a temperature of 35° C. only amounts to
0'02 grm. per hour, while that of water = 3-4 grms. The ratio is
thus 1-200 ; but it varies from hour to hour and more noticeably
from day to day. A ligature applied to the arm produced
increased elimination of carbonic acid (up to 40 per cent) and
diminution in the elimination of water (up to 20 per cent), which
was more pronounced in proportion as the ligature was tighter.
Varnishing the skin with collodion, by which the orifices of the
sweat glands are blocked, causes marked diminution in the
elimination of water (to 78'1 per cent) without entirely abolishing
it. These results, in conjunction with the direct experiments on
the diffusion of water vapour and carbonic acid through thin plates
of horn, led Barratt to conclude that the horny layer also played
an important part in the elimination of water, and that the dis-
charge of carbonic acid through the skin is a process of simple
physical diffusion, which takes place through the whole stratum
corneum independent of the sweat glands.
V. Willebrand's researches (1902), on the other hand, agree
ix THE SKIN AND CUTANEOUS GLANDS 495
perfectly with Schierbeck's results. The subject of experiment
was enclosed in a metal box, so that only the head was outside.
The cutaneous transpiration of the rest of the body was deter-
mined at a temperature of 12-34° C. by estimating the content
of water and carbonic acid in the air that circulated through the
apparatus, and was entirely renewed every five minutes, the
quantity being measured by gasometers, before and after its
passage through the box. He found that when the body was
completely at rest the elimination of water increased slowly, and
in proportion with the temperature of the external air, which rose
from 12° C. to the point at which perspiration broke out, which
occurs between 30° and 33° C.
The elimination of carbonic acid by the skin at a temperature
fluctuating between 20° and 33° C. is unaltered, provided the body
is completely at rest, and amounts to 7-8 grins, in 24 hours. But
when the temperature rises to the point at which sweat breaks out
(i.e. 33° C.) a rapid three- or four-fold rise in the discharge of C02
appears suddenly.
The molecular concentration of human sweat was first studied
by Ardin-Delteil (1900) with the cryoscopic method. He found
that the freezing-point of sweat was always higher than that of
blood, on an average A = 0'237° 0. It varies considerably with
the individual and the time of year : in the summer, when the
sudoriferous glands secrete much water for the purpose of regulat-
ing the temperature, the molecular concentration of the sweat falls
to A = 0'08° ; its maximum, on the contrary, may be A = 0-46°.
These oscillations are principally due to the varying content of
sodium chloride. The fact that sweat has a lower molecular con-
centration than the blood was also confirmed by Strauss (1901)
for the sweat collected from sick people and that obtained by
hot-air baths. The normal hypotonia of the secretion of the
sudoriferous glands, as compared with the normal hypertonia of
the renal secretion, witnesses to the different functions of the two
secretory processes, the former being mainly concerned with
excretion of water, the latter with excretion of the solid products
of metabolism.
Experiments have been made to determine whether the sweat
has any toxic properties (Eohrig, Queirolo, Capitan and Gley,
Cabitto, Arloing, Charrin and Mavrojannis, Mairet and Ardin-
Delteil), but have not led to any consensus of results. Some
authors assert that there is a toxic action, but the majority
entirely deny the toxicity of normal sweat.
IV. When the secretory activity of the sudoriferous glands
rises to the point at which it is manifested in the sensible form
of sweat, it is usually accompanied (as occurs with many other
secretions) by dilatation of the cutaneous vessels. The thermo-
regulatory function of the skin depends fundamentally on this
PHYSIOLOGY CHAP.
association of the two phenomena. In the summer, or in an
overheated atmosphere, the vessels dilate, and cutaneous perspira-
tion increases, after which the body is liable to a chill either from
increased irradiation of heat into the atmosphere, or by increased
evaporation of sweat. In the winter, or in too cold an atmo-
sphere, on the contrary, the skin becomes pale from vascular
constriction, cutaneous perspiration is diminished, and the internal
heat is stored up owing to the lessened dispersion at the surface
of the body.
One of the earliest experiments which unmistakably shows
the coincidence of cutaneous hyperaemia and sweating was that
of Dupuy on the horse (1816), repeated and confirmed by Mayer
(1826), which seems to have inspired Cl. Bernard with the discovery
of the vaso-constrictor nerves in 1851. Division of the cervical
sympathetic in the horse produces a marked and persistent secre-
tion of sweat in the same half of the animal's head, accompanied
with neuro- paralytic hyperaemia. According to Mayer, galvanisa-
tion of the skin of the neck in man, which excites the sympathetic,
reduces cutaneous transpiration when it causes pallor, and increases
it on the contrary, both in the neck and arm, when the skin is
flushed.
This correlation of the two phenomena is, however, neither
constant nor necessary, and countless observations and experi-
mental data show that the secretion of the sweat glands is directly
influenced by secretory nerves, which are quite independent of the
vasomotor innervation. The sweat, e.g. of anguish, the "cold sweat "
of the death-agony, and of many illnesses, particularly of con-
sumption, are associated with anaemia and not with hyperaemia
of the skin.
In his fine researches on the vaso-dilator fibres that run in the
sciatic to the lower limb, Goltz (1875) noted that excitation of
the peripheral end of this nerve, besides hyperaemia, determined
the appearance of sweat drops on the pad of the cat's foot. This
fact was confirmed by Kendall and Luchsinger (1876), who also
found that peripheral stimulation of the brachial plexus excited
sweat drops on the pad of the cat's front paw. They found, how-
ever, that this secretion is not necessarily connected with flushing
of the skin or increased temperature of the foot. With currents
that are not unduly strong the secretion of sweat can be observed
even when the cutaneous surface (which has no hair) becomes pale
and cold. They further saw that sweat can be excited on the pad
of the cat's foot by stimulation of the sciatic 20 minutes after
amputation of the limb, showing absolutely the independence of
the secretion from blood pressure and circulation.
No less important were the results of Ostrumow (1877). He
saw that stimulation of the abdominal sympathetic produced the
same effect on the cat's paw as that of the sciatic, that the effect
ix THE SKIN AND CUTANEOUS GLANDS 497
was not inhibited by ligation of the aorta, but did cease, as in
other glands, after atropinisation of the animal.
Luchsinger (1877) and Nawrocki (1878) confirmed the existence
of sudoriferous fibres in the abdominal sympathetic for the pro-
duction of sweat in the cat's hind-foot, and also found sudoriferous
fibres in the thoracic-sympathetic to the front paw of this animal,
and in the cervical sympathetic to the head of the pig and horse.
The spinal origin of these fibres has been worked out by a
number of observers — Luchsinger, Nawrocki, Vulpian, Ott, and
more recently by Langley (1891). According to Langley, the
sudorific fibres for the cat's hind paw run from the cord to the
sympathetic through the rami communicantes of the last two
thoracic roots and the first three or four lumbar roots. They
connect with the last lumbar and first sacral ganglia, and run in
the grey rami of these ganglia to the spinal nerves which unite
to form the sciatic.
The sudorific fibres to the front paw, according to Langley,
reach the sympathetic by the rami communicantes of the 6th, 7th,
and 8th thoracic nerves; then ascend to the stellate ganglion,
and reach the brachial plexus via the grey fibres of this ganglion,
and pass thence to the median and ulnar nerves.
Besides the secretory fibres for sweat, some authors admit the
existence of antagonistic fibres, i.e. inhibitory to the sweat glands
(Vulpian, Ott, Arloing). But the experimental data adduced are
ambiguous, and do not prove the existence of a double order of
nerves for the regulation of cutaneous secretion. The sudorific
fibres can be excited, and the secretion of sweat promoted, by
exciting the centres from which they emanate. The centres for
the secretory sweat fibres to the hind limbs of the cat are in the
lumbar cord ; those for the anterior limbs in the cervical cord.
On separating the dorsal from the lumbar cord in the cat by
a cross-section, and then placing the animal for a few minutes in
a temperature of 40-45° C., sweating is provoked not only in the
pad of the anterior foot, but in the posterior as well (Luchsinger).
This secretion depends not only on a direct action of the super-
heated air upon the sudoriferous glands, but upon the activity of
the central nervous system. In fact, when the sciatic is previously
divided on one side, no sweat is secreted at the pad of the corre-
sponding foot, although the sweat glands here are exposed to the
action of heat as much as in the three other limbs.
The sweat excited by an asphyxial condition of the blood (as
is probably the case with the sweat of the death-agony) depends
on excitation of the nerve centres, and not on that of the peripheral
apparatus. In fact, if a cat in which the sciatic is divided on one
side is asphyxiated, sweat appears only in the three paws connected
with the centres, and not in that which has been cut off.
Both in warmed and in asphyxial blood sweating may be
VOL. II 2 K
498 PHYSIOLOGY CHAP.
conceived of as a reflex or as a direct excitation of the spinal
centres of sweat secretion. Luchsinger showed that sweating
occurs in the hind paw of a cat in which the cord has been
divided in the middle of the thorax, both with rise of temperature
and in asphyxia, if all the posterior roots below the cross-section
are divided. In this case the sweating must be explained by
direct excitation of the lumbar centres.
Reflex sweating is more easily demonstrated. It is only
necessary to stimulate the central end of the cut sciatic or ulnar
or median nerve to promote perspiration in the three other
paws. The mere sight of a dog makes a cat sweat from all
four feet.
Many interesting phenomena can be observed when poisons
are used to excite or hinder sweat secretion. Certain poisons,
particularly strychnine and picrotoxin, apparently promote sweat-
ing merely by their action on the spinal cord, since they have no
effect on the paw of which the nerves have been divided. Other
poisons, on the contrary, e.g. nicotine and eserine, produce slight
sweating even in the paw of which the nerves are cut ; so that
these drugs stimulate not only the centres, but also the peripheral
apparatus (Luchsinger, Hogyes). Pilocarpine excites a marked
secretion of sweat even when the nerves have been divided, so it
must act upon the nerve-endings in the glands (Luchsinger,
Nawrocki, Vulpian), or on the secretory cells (Max Levy). Even
after degeneration of the cut nerve, the limb can be excited to
perspire by a sufficient dose of pilocarpine. A similar but less
pronounced effect is produced by muscarine (Triimpy and
Luchsinger).
Atropine and duboisine are poisons which have an antagonistic
action to that of pilocarpine and muscarine. Intravenous injection
of 3 mgrms. atropine in the cat will inhibit the secretory effect of
exciting the sciatic. If 10 mgrms. pilocarpine are then injected,
sweating takes place, although excitation of the nerve still has no
effect. In this case it must be assumed that atropine paralyses
the nerve - endings, while pilocarpine excites the secretory cells.
But if 20-30 mgrms. atropine are injected, the paralysis extends
to the secretory cells also, so that local application of pilocarpine
has no effect (Rossbach). That atropine acts not only on the
nerves, but also on the gland cells, by a temporary paralysis of
the secretory function, was elegantly demonstrated by Aubert in
his method of photographing the sweat-prints (Fig. 137).
V. The Sebaceous Glands are distinguished from the Sudori-
ferous, not only by their morphological structure, but still more
by the nature and process of their secretion. They are no less
plentifully distributed in the skin than the former. They are
compound tubular glands, the excretory duct of which runs along
the canal of a hair follicle (Fig. 138). They are therefore most
ix THE SKIN AND CUTANEOUS GLANDS 499
plentiful in the regions beset with hairs or down, and are few in
the parts destitute of hair, and entirely absent from the palm of
the hand and sole of the foot.
Externally the sebaceous glands are pear-shaped or acinar.
They are of unequal size, and are not in proportion with the
thickness of the hair to which they are attached. Those of the
PIG. 137. — Sweat-prints showing suspension of secretion by local application of atropine. (Aubert.
The area Atr.1, to which a sponge soaked in atropine was applied, shows no sweat-prints
Atr.9, which was covered with belladonna plaster, also shows none. The centre, on which a
sponge soaked in plain water was laid, remained unaltered.
alae of the nose and the cheeks are larger than elsewhere, though
connected only with the fine, downy hairs of those parts (Fig- 139).
The epithelial cells which line them are polygonal, and charged
with fat-granules. The cavity of the gland is filled by a granular
mass, the sebum, which lubricates the hairs and the stratum
corneum.
Sebaceous glands are also found in the mucous membrane of
the labia majora and rninora of the vulva, in the clitoris, the
glands and prepuce, and in the eyelid (Meibowmian glands). The
500
PHYSIOLOGY
CHAP.
Pio. 138.— (Left.) Hair follicle, longitudinal section. (Biesiadecki.) a, mouth of follicle ; b, i
of follicle ; c, lower bulbar swelling ; d, e, dermic coat (outer and middle layer ; the inner (
hyaline layer is not seen) ; /, g, epidermic coat (inner and outer root-sheath) ; h, cuticle of
root-sheath ; k, medulla ; I, hair-bulb ; m, fat of subcutaneous tissue ; n, arrector pili ;
o, papilla of skin; p, papilla of hair-bulb; st, Malpighian layer of epidermis : <•/', stratum
corneum, erroneously represented in figure as continuation of inner root-sheath ; t, sebai'cmis
gland.
Fio. 139. — (Right.) Longitudinal section of a sebaceous gland from the cheek, with r. small hair
growing through its duct. Human. (Toldt.)
ix THE SKIN AND CUTANEOUS GLANDS 501
largest are in the alae of the nose and the red margin of the lips
near the angle of the mouth.
The sebaceous content of the glandular spaces is fluid, and
consolidates into a semi -soft yellowish mass during its passage
through the duct, so that it can sometimes be squeezed out,
particularly at the nasal pinnae, in the shape of a vermiculus.
The ceruminous glands of the external auditory meatus are coiled
glands. But there are also true sebaceous glands in connection
with the hairs of the auditory meatus, to which, exclusively, some
authors attribute the secretion which lubricates this duct.
Under the microscope the sebaceous secretion shows innumer-
able fat-granules, cells in fatty degeneration, crystals of cholesterol,
and almost invariably microscopic acari (demodex folliculorum).
Chemical examination shows the presence more particularly of
neutral fats, soaps, fatty acids, cholesterol, a small quantity of
protein, casein, and extractives of an undetermined character. In
the minerals insoluble earthy phosphates, chlorides, and alkaline
phosphates predominate.
The vernix caseosa which covers the skin of the foetus comes
from the accumulation of the sebaceous substance secreted during
intra-uterine life, mixed with detritus of macerated epidermal and
epitrichial cells. According to Liebreich and Euppel it contains
cholesterol, oleic and palmitic acid, and their respective glycerides.
It facilitates the progress of the foetus along the vagina in delivery.
The smegma preputii is analogous to the foetal vernix caseosa,
and contains a specific compound of ammonia, on which the
odour peculiar to this secretion depends. The substance known
as castoreum is the secretion from the sacculated prepuce of the
beaver ; it has a characteristic odour, and is employed as a sedative
in medicine. It contains resinous substances, benzoic acid, and
other aromatic compounds.
The wax or cerumen of the auditory meatus, in addition to
specific fats of a waxy consistency, contains a specific bitter
extractive. The secretion of the Meibowmian glands does not
differ from that of the cutaneous sebum, and lubricates the eye-
lashes. It tends to collect along with the tears in the inner angle
of the eye, where it is entirely or partly absorbed, and is carried
off with the former by the lachrymal duct.
All these secretions have a protective function which is quite
distinct from that of perspiration. Their mechanism is also very
simple, and quite different from that of other secretions. The
ordinary secreting cells elaborate the material of their secretion
without being destroyed in the process ; the young cells of the
sebaceous glands, on the contrary, multiply incessantly by karyo-
kinesis (Bizzozero and Vassale), while the older cells undergo fatty
degeneration, until they drop off and mingle with the sebaceous
substance collected in the cavity of the gland.
502 PHYSIOLOGY CHAP.
The formation of sebum is therefore not so much the result of
a true secretory process as of the perpetual renewal and fatty
degeneration of epithelial cells, — perfectly analogous to the renewal
of the stratum corneum of the epidermis, in consequence of the
keratinous degeneration of the cells of the Malpighiah layer.
Nothing definite is known as to the influence of the nervous
system on the sebaceous glands. It would not be surprising if,
like the glands of plants, they function independent of any regu-
latory nervous influence. Yet .certain observations of Arloing
(1899) suggest they are probably no exception to the general rule.
After dividing the cervico-sympathetic in the donkey, he saw that
a quantity of wax collected in the sebaceous glands of the skin
of the ear, which reached its maximum 15 hours after section,
and ceased about 64 hours after. Excitation of the peripheral
end of the nerve also seems to cause a perceptible increase in the
secretion of these glands.
VI. The Mammary Glands, from which the highest class of
vertebrates has been named, belong to the skin no less than the
sudoriferous and sebaceous glands.
They are compound acinar glands which may be regarded as
a collection of enlarged sebaceous glands with modified functions.
In man there are only two, in the region of the breast ; in the
mare and the goat two, and four in the cow, in the lower abdominal
region ; multiparous animals have ten, twelve, or even more along
the abdominal wall. From the phylogenetic point of view it is
important fact that in many of the lower mammals of the Monotre,
group the mammary glands consist of a large number of sma
cutaneous glands without a nipple, which resemble enlarge
sebaceous glands. The new-born offspring are nourished by licl
ing the region of the maternal abdomen in which these glands
situated. For the rest we have seen that the secretion of even tl
ordinary sebaceous glands contains a small amount of caseinogei
which confirms the phylogenetic homology between sebaceous am
mammary glands (Neumeister).
The development of the mammary glands commences in botl
sexes in the third month of intra- uterine life. At birth the
glandular tissue consists of tubes which branch two or three time
and terminate in a blind sac. At the twelfth year these tul
subdivide into more branches, but the glandular alveoli at tl
extremity are not developed till the approach of puberty in
female.
In males the mammary gland is only a rudimentary, vestigu
organ, witnessing to an original hermaphroditism. In the adi
they are no more developed than in the foetus. At the age
puberty they may develop to a certain extent and harden, b
immediately undergo a process of degenerative involution. New-
born animals of both sexes constantly secrete a small quantity of
ix THE SKIN AND CUTANEOUS GLANDS 503
milk for a few days, which is popularly known as " witches' rnilk."
The mammary secretion may occur (though very rarely) in adult
males, in virgins, and in females who have not conceived, are not
pregnant, and not in labour. Talmud, Cardauo (1556), Fiorentino
(1553), A. V. Humboldt, Haeser, all cite authentic cases in which
the male gland secreted. Degeneration or involution of the gland
takes place in women after the menopause.
During its maximal development, which coincides with the
period of suckling, the glandular mass of the female breast consists
of some twenty distinct lobes, held together by fibrous and areolar
tissue, interpenetrated by accumulations of adipose tissues. Each
lobe is a distinct gland, with a galactophorous or milk duct opening
by a separate orifice on to the summit of the mammilla. Before
branching, each milk duct dilates considerably to form an ampulla
or sinus, which serves as a temporary reservoir for the milk. Each
lobe divides into smaller lobes, and these again into lobules, con-
sisting of a collection of alveoli or terminal acini, into which the
minute lactiferous ductules open. The alveoli often present lateral
enlargements and sometimes (as in the pulmonary alveoli) com-
municate inter se by the breaking-down of the septa, so that larger
cavities are formed.
The walls of the alveoli consist of a basement membrane, having
on its inner surface a layer of flattened stellate cells, which
embrace the gland cells like a basket. The glandular epithelium
is a single layer of cells, which vary considerably in form according
as they are at rest or active, whether the alveolus is dilated or con-
tracted, and so on. We shall subsequently return to the signifi-
cance of these differences.
The secretory ducts have longitudinal fibres of plain muscle
continuous with those present in the skin of the nipple. For the
greater part of their course the ducts are lined with a single layer
of columnar cells, except the principal ducts which run to the
nipple, and are lined with scaly, stratified epithelium.
The arterial vessels enter at different points and form a capil-
lary network round each alveolus; this is continued into veins
which surround the base of the nipple in Haller's circulus venosus.
The lympbatic vessels also, which directly convey the materials of
the lacteal secretion, surround the alveoli, and communicate with
numerous in tra- alveolar lymph sinuses containing a number
of leucocytes, some of which penetrate through the basement
membrane to the interior of the alveoli. The nerves running to
the mammary gland are branches of the intercostal and supra-
clavicular nerves. They proceed partly to the skin of the nipple,
partly to the muscular fibres of the ducts, the blood-vessels, and
the glandular acini where their endings have not yet been
determined.
VII. Human Milk is a white or yellowish fluid, opaque, without
504 PHYSIOLOGY CHAP.
odour, and with a peculiar, sweetish taste. Its specific gravity
varies from 1-Q25 to 1-034. In the fresh state it gives the same
reaction as cow's or goat's milk, i.e. slightly alkaline or arnphoteric,
while the milk of carnivora is faintly acid. If left to stand, a
yellowish layer, the cream, forms on the surface. In time it turns
sour or clots, by lactic fermentation.
The percentage composition of human milk is very variable.
From the average of a great number of analyses carried out by
Pfeiffer and Leed, it contains 10'8-13 per cent solid constituents.
These are organic and inorganic. The organic are represented by
the three principal groups of food-stuffs — proteins, fats, and carbo-
hydrates.
The proteins are present to an amount of l'6-2'5 per cent.
The chief protein is caseinogen, a phosphorated substance belonging
to the nucleo-proteins, which has the property of clotting when
acted on by chyrnosin or rennin (Chapter II. p. 118). There is
further a lact-albumin which closely resembles serum-albumin,
as well as other proteins, e.g. lacto-globulin, lacto-mucin, etc.
Some authors claim also to have detected a small amount of
protease and peptone in human milk, which has been disputed by
Dogiel and Hofmeister. If milk is filtered at high pressure
through a porous filter, the caseinogen is held back, while the
albumin passes, and can be precipitated by heating the filtrate.
It is not definitely known whether the skin which forms on the
surface of milk on boiling really represents protein contained in
the milk. It forms again as often as the first skin is removed.
It is probably an albumin or globulin formed during heating by
alteration of the caseinogen.
The fat of milk forms a perfect emulsion, the droplets as seen
under the microscope being 2-5 //, in diameter, the so-called milk
globules. The stability of this natural emulsion depends on the
fact that each fat-globule is surrounded by a layer of caseinogen
solution which prevents the drops from fusing. If milk is treated
with caustic soda, and then with ether, the caseinogen is precipi-
tated, and the fat runs into large drops.
When milk is allowed to stand, the fat-globules, which are
lighter, mount to the surface and form the cream, and if this be
skimmed off the milk loses a large amount of its butter. The
opacity of milk is due to the fatty globules. When the cream is
removed, the milk that remains has a higher specific gravity than
the natural milk. By centrifuging, milk can be almost entirely
deprived of its fat and becomes semi-transparent.
Milk-fat is a mixture of all the animal fats. Palmitin, stearin,
and olein preponderate ; but they are always accompanied by
small quantities of butyrin and other glycerides. Generally
speaking, it may be said that the fat of milk resembles that of
adipose tissue ; its composition varies like the latter in different
ix THE SKIN AND CUTANEOUS GLANDS 505
animals, particularly in the proportion in which the olein, palmitiri,
and stearin are present. Human milk contains twice as much
olein as it does palmitin and stearin ; in cow's milk the three
glycerides are present in approximately equal amounts. In human
milk the fat content varies from 2'5-4'3 per cent, while in cow's
milk it may amount to 6 per cent.
The carbohydrates of milk are lactose or milk sugar, which is a
disaccharide, and splits on absorption of water into two mono-
saccharides, dextrose and galactose. By means of an enzyme which
is apparently pre-formed in the milk or forms in it on standing, or
by the bacteria from the air, lactose undergoes lactic acid ferment-
ation, by which milk turns sour and clots, the lactic acid which
is formed neutralising the alkali which holds the caseinogen in
solution. Lactose does not ferment like glucose on merely adding
yeast. But there are special bacteria which produce an alcoholic
fermentation with formation of a small amount of lactic acid.
This is utilised for the preparation of kumis from the milk of
mares, and Jcefir from that of cows, which are much used in Russia.
According to bacteriologists these fermented milks are due to the
symbiotic action of two different microbes, a blastomycete (saccharo-
mycete) which produces alcoholic fermentation, and a schizomycete
which causes the lactic fermentation of lactose (Gorini).
Lactose is more plentiful in human milk than in cow's milk ;
in the former it oscillates between 5'5 and 6'9 per cent, while in
cow's milk the average is 4'8 per cent (Konig). Another difference
between the two kinds of milk is that human milk is richer in
lecithin, and poorer in mineral constituents, especially in lime and
phosphoric acid — it contains about ^ the lime and | the phosphoric
acid of cow's milk.
Of the inorganic salts it is remarkable that potash and
phosphoric acid preponderate over sodium or chlorine, as is also
the case in the blood corpuscles and the muscles.
A copious literature in regard to the constituents and
physiological properties of milk has recently sprung up ; it is
chiefly concerned with the study of milk by new methods learned
from physical chemistry and bacteriology. Milk serum has been
investigated on the same lines as the various blood serums with
regard to its bactericidal, haemolytic, and other properties. No
final or even general conclusions have been arrived at, but the
specific character of each kind of milk has been demonstrated,
confirming the old adage, that "mother's milk is a treasure
impossible to replace " (Seiffert).
This rapid survey of the chemical composition of milk brings
out the fundamental fact that this secretion is a chemical
elaboration by the secretory cells of the mammary gland, and not
a mere transudate of the blood or lymph circulating through it,
as was formerly held. Caseinogen is rarely present in the blood ;
506 PHYSIOLOGY CHAP.
fats are there in minute quantities only, whereas they are
abundant in milk ; lactose is not found at all in blood ; lastly,
the inorganic constituents of milk and blood are quantitatively
different.
The yield of milk from the body in 24 hours is generally
considerable. During well-established lactation a good wet-nurse
will produce a litre or a litre and a half per diem. This amount
may be greatly increased since it depends on a number of
factors, the principal of which is the degree of development of
the mammary gland. Interesting observations on this subject
have been made on the cow. Two cows of the same breed and
approximately the same weight produce very different quantities
of milk, in proportion with the development of the udder. Accord-
ing to Fleischmann the maximal yield from a milch cow is 24
litres = 25 kilos, milk per diem, with about 3 kilos, solid substances.
Since the maximal weight of the udder is about 5 kilos, with
1'5 kilos, solid substances, it follows that in these extreme cases
the udder secretes five times its own weight in the day.
The development of the gland, which is maximal during the
first weeks after parturition, diminishes with the duration of
lactation, and the yield of milk decreases in proportion. The
influence of race upon the development of the udder and con-
sequently of its yield of milk is great. The best milch cows are
those of the Swiss, Dutch, and Oldenburg breeds. According to
Fleischmann muscular work, within certain limits, conspicuously
diminishes the lacteal secretion, and in time determines a certain
amount of glandular involution. This is why the race of cattle
employed in heavy agricultural labour give little milk.
VIII. In order to form an idea of the process by which the
mammary gland forms the specific constituents of milk, which do
not pre-exist in blood and lymph, we must examine the effect of
nutrition in general, and of specific diets in particular, upon
lacteal secretion.
It is only necessary to compare the amount of organic
substances contained in milk with a scanty and an abundant diet,
to see the great influence of alimentation in general upon the
functional activity of the mammary gland. Every one knows
that a wet nurse must be well fed in order to have good milk,
which in physiological language means that the crude materials
furnished by the blood and lymph to the mammary gland for the
production of milk come for the most part directly from the food.
It is, however, far more important to see how the chemical com-
position of milk alters with a preponderance in the diet of protein,
fat, or carbohydrate. A priori one would suppose that there
would be a ratio between the quantity of protein, fat, and carbo-
hydrate ingested and the amount of the same in the milk.
Experiment shows, on the contrary, that a diet rich in protein not
ix THE SKIN AND CUTANEOUS GLANDS 507
only improves the yield of milk as a whole, but also the amount
of its principal constituents, particularly the fat content.
This fact was established in 1846 by Franz Simon, for nursing
women, and confirmed by Decaisne in 187.3. Still more striking
results were obtained by Ssubotin (1866), on comparing the
chemical composition of the milk of a bitch fed on meat with one
fed on potatoes only.
The fact that a full flesh diet largely increases the fat content
of milk supplied a valid argument in favour of the theory specially
sustained by Voit, that animal fat is mainly derived from protein.
The secretory cells of the mammary gland principally employ
protein as the material from which they elaborate the organic
constituents of milk. A full protein diet first develops or increases
the secreting cells and the size of the gland, and then the total
quantity of the secretion and its fat content increase also. The
effect is not seen at once, but after a few days, and it is more
pronounced in the early months of suckling than in the later,
when the gland begins to undergo a slow process of involution.
Once the gland has been developed, a smaller amount of alimentary
protein suffices to maintain its increased function.
The effect of a protein diet upon the sugar content of milk
has been much disputed. According to the experiments of
Ssubotin on bitches, and of Kiihn on cows, the lactose is somewhat
diminished ; but according to I. Munk's later experiments (1881),
full protein feeding augments not only the fat and protein content
of milk, but the amount of sugar also.
A full diet of fats not only does not increase the fat content
of milk but even diminishes it, if the food does not contain a
sufficient amount of protein at the same time. In the latter case
there is an increase of butter such as occurs on a richly nitrogenous
diet. From this it may be deduced that the ingested fat does not
tend to increase the fat of the milk, but, by sparing the nitrogenous
consumption, makes it possible for the protein to be utilised more
largely for the formation of butter, as shown by the admirable work
of Pettenkofer and Voit, to which we shall have to refer below
in speaking of general metabolism. That increase of alimentary
fat, with a constant amount of alimentary protein, does not increase
the amount of butter in the milk, is directly proved by Kiihn's
investigations with cows.
The amount of carbohydrate fed has no appreciable effect on
the amount of lactose secreted by carnivora. But even in herbi-
vora no relation can be observed between the quantity of ingested
starch and the sugar content of the milk. Since, as a rule, a
starchy diet coincides with scarcity of protein food, it follows that
the secretory cells of the gland find little material to hand for the
formation of the milk as a whole. That not only the fat but also
the lactose (for the most part at any rate) come from the protein
508 PHYSIOLOGY CHAP.
circulating with the lymph in the gland, is seen from the fact that
bitches fed with an exclusively flesh diet excrete large quantities
of sugar in their milk (Ssubotin). It is therefore a mistake to
feed wet nurses on thick soups and farinaceous foods, with the
object of increasing the supply of milk. Protein substances should
be the basis of a rational diet for nursing women.
Starting from the hypothesis that the lactose of the milk
originates in a process of conversion by the secretory gland-cells of
the dextrose of the blood, P. Bert (1884) excised the udder of a
goat, after which she became pregnant and gave birth. For three
days after parturition, the urine contained sugar, since it reduced
cupric oxide. To account for this transitory glycosuria he assumed
that after parturition glucose was normally formed more abundantly
than usual, and was converted into lactose in the mammary gland.
As the udder had been excised in the goat experimented on, the
puerperal hyperglycaemia gave rise to glycosuria. But it seems
to us far simpler to account, for the fact observed by Bert, by
referring the temporary glycosuria to injuries of parturition. In
any case it would be advisable to check the fact, by determining
what kind of sugar was present, and otherwise extending and
varying the experiment. We know from Hofmeister (1878) that
the urine of women and mammals in general often contains
lactose immediately before and after parturition, which is due
presumably to reabsorption of the lactose formed by the cells of
the mammary glands.
Paul Bert's experiments were repeated by Porcher in 1905
with the same results. He further found that cows, goats, and
bitches into which glucose is injected in small doses subcutaneously,
or by the peritoneum or mammary gland, are capable of excret-
ing it during lactation as lactose in the urine, which lends support
to the view that the mammary glands really effect a conversion of
glucose into lactose. Piantoni (1908) came to the same conclusion,
on studying the effect on the lacteal secretion of a milch goat of
the subcutaneous injection of various sugars (lactose, galactose,
glucose-, saccharose, raffinose, and dextrin).
According to C. Foa and Andreoni (1908) there is no percentage
difference in the content of the substances (glucose, glucoproteins,
glycogen) from which lactose originates, in the blood of women
who are suckling and not suckling. On comparing the content of
these substances in the carotid blood with that of the blood that
has traversed the gland, he finds a marked diminution in the
latter of free glucose and of that which is combined with the
proteins, while the glycogen is not diminished.
IX. The exact cytological and chemical mechanism by which
the milk is secreted from the epithelial cells which line the alveoli
of the mammary gland, is still a matter of dispute.
It was formerly held that the milk is discharged, on analogy
ix THE SKIN AND CUTANEOUS GLANDS 509
with the secretion of the sebaceous glands, by the disintegration
and liquefaction of the older cells, in proportion as new cells
replace those destroyed and converted into milk. This view rests
on the common origin and homology of the two kinds of glands.
It also finds support in the theory that prevailed as to the origin
of the colostrum corpuscles found in the first milk, which is secreted
in the last days of pregnancy and the first 3-4 days after parturi-
tion. The colostrum corpuscles are true cells, mostly nucleated,
round, and very granular. By some they have been regarded as
modified gland cells, which become detached and pass into the
secretion previous to complete disintegration, which they undergo
later, when colostrum corpuscles are no longer present in the milk.
As soon as the mammary glands are excited to activity, the
alveolar cells fill with granules and globules of fat, and the
alveolar spaces with a clear fluid in which fat globules and
occasional colostrum corpuscles are seen to float.
The colostrum corpuscles, however, have not the appearance of
epithelial cells, and on the warm stage of the microscope they
exhibit amoeboid movements similar to those shown by leucocytes.
They are therefore supposed by many to be leucocytes that have
wandered from the lymph sinuses of the perialveolar tissue into
the lumen of the alveoli, and not cast-off epithelial cells.
The theory that milk is formed by regeneration of the epithelial
cells is discounted by the fact that no such rapid and persistent
cell-multiplication can be detected in the mammary gland as
would account for the organic constituents of the milk, on the
theory of detritus from disintegrated cells. Heidenhain, indeed,
calculated that the gland-cells would have to be renewed at least
five times in every 24 hours, if they are to provide the solid
materials of the milk.
Partsch (1880) advocated another view, which was accepted
by Heidenhain. According to this, the secretion products formed
in the gland become gradually accumulated at the free ends of
the cells, which lengthen out and become columnar, projecting
unequally into the lumen of the alveolus. The enlarged free end is
supposed to become detached, and discharge the accumulated
products, while the outer part of the cell (with the nuclei) remains
intact, and repeats the same process.
In support of this hypothesis they adduce certain histological
researches carried out on the mammary gland of the bitch in
different phases of secretory activity (Fig. 140). At the commence-
ment of lactation the alveoli were distended by a clear secretion,
in which fat globules and a few colostrum corpuscles floated.
The epithelium was flattened against the basement membrane, and
contained fatty globules of various sizes. During full secretory
activity, on the other hand, i.e. when lactation was fully developed,
the cells became first cubical and then columnar, and vary in size ;
510
PHYSIOLOGY
CHAP.
they projected irregularly into the lumen of the alveolus, had
usually two or three nuclei, and contained fatty globules
similar to those of the milk, at the end which projected into
the lumen.
Later work on the mammary gland in full secretion did not
confirm these observations. Generally speaking, the epithelial
cells are uniformly flat or at most cubical, as shown by Fig.
141. Schafer regards it as probable that the columnar appearance
described by Partsch and Heidenhain is found only in collapsed
alveoli, due to the deformation of the basement membrane. On
the other hand, the same argument which Heidenhain urged
against the first view can with slight modifications be adduced
FIG. 140.— Alveoli of mammary gland of bitch under different conditions of activity. (Heidenhain.)
a, b, section through the middle of two alveoli at the commencement of lactation, the epi-
thelium cells being seen in profile ; c, part of the wall of an alveolus in a similar condition,
with epithelium cells seen flat; <7, alveolus in full secretory activity.
against his own, which assumes the formation of the milk to
depend upon disintegration of the projecting, non-nucleated part
of the cell protoplasm. The regeneration of the protoplasm lost
by secretion would have to be so rapid that we know of no
analogous phenomena to give countenance to it.
Since in all the other glands we have been studying the
secretory process takes place without any cellular destruction or
regeneration (except in the case of the sebaceous glands, the
function of which is no true secretion), it is difficult to see why
the simplest hypothesis should not also be accepted for the
lacteal secretion. According to this the epithelial cells of the
mammary gland have the power of forming the specific organic
constituents of milk from conversion of the crude materials drawn
from the lymph, not by any cytological process that involves the
disintegration of the protoplasm, but by an essentially chemical
method, the exact nature of which is unknown to us, — as in the
IX
THE SKIN AND CUTANEOUS GLANDS
511
case of all the other secretions. This does not preclude the multi-
plication of cells during the active secretory work of the mammary
gland to an extent in excess of the normal, but at present we
know nothing as to the exact manner in which this is accomplished.
According to Steinhaus (1892) there is frequent mitotic division
of the cell nuclei without subsequent cellular division, accom-
panied by transformation of the nuclear substance into fat— which
would explain the origin of the fat of milk. Szabo (1896), on the
Pio. 141. — Section of lobule of mammary gland of guinea-pig during lactation. (Szymonowicz.)
olv, lumen of alveolus ; mp, membrana propria ; ep. olv, alveolar epithelium, tangential
section ; <jl, gr, fat drops stained o.srnic acid.
contrary, observed no mitosis during lactation, but an a-mitosic
multiplication of nuclei, so that each cell contained two or three.
He also found a great accumulation of protein granules in the
cell protoplasm, which gradually pass into the secretion and
become dissolved.
In all probability these granules are the nucleo-gluco-protein
which Hammarsten (1894) found in the protoplasm of the
mammary gland, and which probably represents the mother
substance of the caseinogen and lactose. In fact, Thierfelder
(1883) saw that on grinding up fresh mammary gland in physio-
logical saline, and leaving it to digest for some time at body
512 PHYSIOLOGY CHAP.
temperature, caseinogen and lactose were formed. The latter is
preceded by the formation of a colloidal carbohydrate which is
identical not with glycogen, but, according to Landwehr, with
animal gum. These observations agree with what wre have stated
in regard to the preponderating importance of alimentary protein
for milk production, and the amount of the respective organic
constituents of milk. We may reasonably conclude that the
mammary gland obtains from the serum-albumin of the lymph,
more particularly, the material for the synthetic formation of the
nucleo-protein and gluco-protein of which its protoplasmic granules
are composed. The different specific constituents of the milk
are derived from the decomposition of these and of the nuclear
substance.
Arnold's subsequent work (1905) on the formation of the fat
of milk also gave results that entirely agree with the above view.
On studying the mammary gland of woman, cow, and rat under
the microscope, he saw that a copious secretion of fat could occur
without cellular degeneration ; that the fat always appeared first
inside the cell, in place of the granules of the cytoplasm (particu-
larly in the basal part opposite the lumen), while fat was never
seen round the cells. The mother substance of the fat must there-
fore be supplied to the cells in a dissolved form, which is after-
wards converted into fatty granules by the protoplasm.
As regards the colostrum corpuscles, on the contrary, Popper
(1904) fell back on the conclusion that they are epithelial cells
detached from the alveoli or ducts, which on reaching the lumen
of the gland are still capable for a certain time of showing vital
phenomena, before they undergo fatty degeneration. Their origin
as gland cells is shown more particularly by the aspect of their
nuclei, which exactly resemble those of the gland cells, and are
clearly distinguished from those of the leucocytes by the reticular
arrangement of the chromatin. These and other data militate
against the foregoing view by which the colostrum corpuscles are
taken to be leucocytes.
X. The evidence as to whether the secretion of milk is directly
or indirectly influenced by the nervous system, is of a conflicting
nature. Generally speaking, it may be said that a number of
everyday observations demonstrate the intervention of the
nervous system both in the development and in the secretory
activity of the mammary gland.
The correlation between the genital apparatus and the
mammary glands is familiar to every one. The latter develop
gradually during gestation ; immediately after parturition the
milk secretion becomes very abundant, and persists throughout
the period of suckling. Moreover, during this period menstruation
usually ceases. These facts witness to a special trophic and
functional relation (a sympathy as was formerly said) between
ix THE SKIN AND CUTANEOUS GLANDS 513
the genital organs and the mammae, due in all probability to a
reflex nervous influence between the two organs.
Nothing but a reflex nervous excitation can explain the fact
that periodic suckling or milking is necessary to keep up the
lacteal secretion. In order to stop it, either in the first days after
parturition or at any subsequent period of suckling, it is only
necessary to interrupt the periodic evacuation of the gland.
When the gland spaces have been emptied they gradually fill
up again, rapidly at first, and afterwards more slowly, until at
a certain degree of tension the secretion ceases entirely, and the
milk is gradually reabsorbed. It is certain that sucking at the pap
or milking the udder does not merely empty the gland of the
milk already secreted, but also reflexly promotes the further
secretion. According to Heidenhain, the glandular spaces of the
udder of a good milch cow have a capacity of about 3000 c.c., this
being the difference in volume before and after evacuation. A
Swiss cow is known to yield a quantity of milk far in excess of
3 litres at a single milking. It is therefore clear that the milking
not merely empties the udder, but also activates the secretion
of new milk. This is also proved by the fact that frequent
milking considerably increases the yield of milk in a cow, but it is
not advisable to trade upon this fact, since the animal's general
nutrition would deteriorate.
Lehmann (1887) injected a solution of indigo-carmine (sodium
sulphindigotate) into a milch goat, and at once began to milk her.
The first milk kept its colour, then it became slightly tinged, and
(after the lapse of an hour or an hour and a half) it became a
definite blue. This proves that the secretion is promoted by
milking.
Another proof of nervous influence on the milk secretion is
seen in the fact that milking causes considerable alteration in the
composition of the secretion. "While the glands are emptying the
fat content increases, and that of caseinogen diminishes. Accord-
ing to Eeiset the difference between the first and second milk is
greater in proportion with the interval between the two milkings.
This phenomenon seems to us inexplicable, unless it be admitted
that the mechanical stimulation of the teat exerts a reflex trophic
action on the secretory cells.
Certain observations of Baglioni (1907) agree with the above.
In a nursing woman he saw that when the child was put to one
of the breasts and began to suck greedily (especially when the
breasts were very full), a copious gush of milk came spontaneously
from the other breast. Evidently this is a reflex, in which the
stimulation of one breast excites secretion in the opposite breast
also, either by increasing the secretory activity, or by producing
a contraction of the plain muscular fibres of the milk ducts, on
which the milk is ejected. That such a phenomenon really takes
VOL. II 2 L
514 PHYSIOLOGY CHAP.
place conspicuously in the breast, and may effectively co-operate
in the efforts ' of the child to suck by jerking the milk out of the
ducts, especially when the breast is full, can be seen by removing
the infant shortly after it has begun to suck greedily. The orifice
of the nipple will continue for some time to excrete the maternal
milk.
Sudden mental emotions readily produce an inhibitory effect
on the secretion of milk. In anger or fear it is soon suppressed.
Mental suffering may diminish the secretion, or alter its com-
position to such an extent that it is insufficient, or even becomes
harmful to the infant.
It is thus a matter of common experience that the nervous
system regulates the milk secretion, and promotes or moderates it,
not by any simple vasornotor action, but by a trophic or secretory
influence.
Nevertheless, the physiological experiments undertaken in the
hope of confirming these empirical observations by the discovery
of the nerve paths and centres of lacteal secretion have so far led
only to negative or contradictory results.
Eckhard (1858) was the first who experimented in this direc-
tion. He saw in goats that neither division nor excitation of the
external spermatic nerve which innervates the udder of tht
animals produced any sensible effect on the milk secretion ; it
was unaltered in the udder both on the side operated on and 01
that which was left intact. His observations have been repeat
by others with positive, but often contradictory results.
Eohrig (1876), in order to study the rate of the lacteal flow ii
the goat, introduced into the excretory duct (which is solitary
this animal) a fine catheter, pushing it up beyond the milk sinus,
and connecting it at the free end with an aspirating vessel.
this means he obtained a regular flow of milk at a rate of about
2 drops per minute, if the goat kept still, while 8-10 drops
minute escaped if the animal was restless. To obviate the
turbing effect of moving, he curarised the animal, which did not
alter the rate of secretion. On cutting or faradising the separat
branches of the external spermatic nerve under these experiment
conditions, he obtained results which led him to admit the existenc
of:—
(a) Sensory nerves capable of inducing reflex movements
(6) motor nerves, which cause erection of the nipple and tonic
contraction of the muscular fibres of the lactiferous ducts; (c)
vasornotor nerves, section of which produces acceleration of the
secretion, peripheral stimulation its delay.
He held the presence of specific secretory nerves in the mammal
gland to be improbable. But in Heidenhain's opinion the experi-
ments described by Eohrig are not sufficiently numerous or con-
clusive to make his evidence irrefutable.
ix THE SKIN AND CUTANEOUS GLANDS 515
Laffont (1879), on repeating Bohrig's experiments on curarised
goats, came to the opposite conclusion, viz. that the milk secretion,
like many other secretions, is under the simultaneous control of
secretory and of vaso-dilator nerves.
Hammerbacher (1884) studied the effect of pilocarpine and
atropine injection on the lacteal secretion of the goat. In animals
kept on a constant diet, he found that subcutaneous injection of
3-15 cgrms. pilocarpine caused no perceptible increase in the milk
secretion, while a few hours after injection of large doses of this
drug the secretion was reduced, and the milk also contained fewer
solids.
Atropine, on the contrary, even in small doses diminishes the
secretion of milk, while the content of solids, particularly the
percentage of fat, was much increased. This effect of atropine is
borne out by the clinical fact that it is successfully used to stop
the secretion of milk in nursing women.
Valentowicz (1888), who continued Eohrig's experiments on
goats, found that the stimulation of the peripheral end of the
external spermatic diminished the secretion instead of increasing
it. But after dividing this nerve on one side, the difference in
the amount of secretion, and also in the composition of the milk
on the two sides, is not very marked. He noted, however, that
after some time there was a certain increase in the amount of milk
secreted and the fat content, on the operated side (paralytic
secretion). If milking was discontinued in both udders for several
days and then resumed, the secretion was found to be much less
in the normal mamma, than in that of which the nerve had
been cut out. He concluded that the external spermatic nerve
(as a whole) is an inhibitory nerve for the milk secretion.
To us the experiments of Mironow (1894), also on goats, seem
more important. He wished to confirm the clinical fact that
sudden excitation of the nervous system and sharp mental
emotions diminish or temporarily suppress the function of the
mammary gland in nursing women. The milch goat was kept
on a constant diet, and milked twice a day so as to reach a certain
maximum of secretion. On the day before the experiment and
after obtaining this result, the goat was milked every 2-3
hours from the morning till night. The same 2-3 hours' milking
was repeated on the day of the experiment, but on that day a
sensory nerve to the hind leg (the saphenous nerve) was exposed,
raised by a thread, and excited with an induced current of increas-
ing strength for 30-60 minutes, on which the animal showed
symptoms of acute pain, agitation, tachypnoea, etc.
In twenty -four experiments of the same kind, on different goats,
Mironow invariably obtained a considerable diminution in the
secretion of the milk, for a longer or shorter time, in direct relation
with the intensity and duration of the pain.
516 PHYSIOLOGY CHAP.
This result cannot be explained as a simple modification of
the blood circulation in the mammary gland, not only on account
of the time the pain lasts (which may be six hours), but also
because not only the quantity but also the quality of the milk is
altered : it becomes thicker and contains a larger amount of solids,
due particularly to increase of fat.
Mironow further confirms Eckhard's observation that unilateral
section of the external spermatic nerve at the point at which it
leaves the pelvis has no appreciable influence on the total yield
of milk, nor upon the amount of milk secreted by the gland
operated on.
But he adds two important observations, as follows : (a)
bilateral section of the external spermatic reduces the total yield
of milk by more than half (57 per cent) ; (&) the depressing action
of the pain after the bilateral division of these nerves continues,
showing that it is transmitted to the mammary gland by other
nerve paths.
These nerve paths, according to Mironow, are represented by
nerve fibres that enter the mammae along with the branches of
the inferior epigastric vein and artery, and which he terms the
inferior epigastric nerves ; and further by a branch of a nerve
that accompanies a vein which ascends in the symphysis of the
pubes, and then divides into two branches to the two udders,
which he terms the azygos nerve.
In excising these nerves as well as the external spermatics, so
as completely to isolate the mammary gland from the central
nervous system, Mironow did not succeed in suppressing the
lacteal secretion, but only in reducing it to about 35-45 per cent.
He also noted that after thus isolating the glands from the
central nervous system, the pain provoked by protracted sensory
excitation no longer affected either the quantity or the quality
of the milk. The inference is that the mammary gland must
have peripheral nervous centres which control the secretory
activity independent of the higher centres.
A goat in which all the nerves to the udder had been cut
became pregnant and gave birth to two kids. The secretion of
milk increased during pregnancy, and after parturition gradually
regained almost the normal quotum obtained before the operation.
This led Mironow to think that the effect of pregnancy and
parturition on the development and secretion of the mammary
gland was not exerted reflexly by the brain and spinal cord, but
by the peripheral intermammary centres, possibly by modifica-
tions in chemical composition of the circulating fluids, due to a
special internal secretion of the uterus.
Later physiological experiments confirmed the correlation
between the mammary gland and the genital organs. Halban and
Knauer (1900) saw that excision of the ovary was followed by
ix THE SKIN AND CUTANEOUS GLANDS 517
arrested . development or atrophy of the uterus ; Foges (1905)
showed by experiments on young rabbits and kittens, that the
development of the mammary gland is connected with the presence
of ovaries capable of functioning, while the presence or absence of
the uterus was immaterial. On the other hand, Pfister (1901)
observed a reflex influence of the mammary glands upon the
genital apparatus, excitation of the former causing secretion in
the genital organs, return of menstruation, and so on.
All these investigations into the innervation of the mammary
gland await confirmation and development by further research.
Eibbert (1898) made a number of experiments with the object
of investigating the development of the mammary gland during
pregnancy.
According' to this author the development of the gland is not
controlled by the nervous system, because in a case of transplanta-
tion of a mamma from a virgin rabbit into a pregnant one, the
transplanted gland developed mammary functions.
These results, according to most authors, prove definitely that
glandular development occurs by a chemical stimulus or hormone
carried in the blood. But it must be remembered that Eibbert
alone, and in one single case, obtained a positive result ; all the
control researches have so far proved negative.
By another method Lane-Claypon and Starling arrived at a
theory in accordance with that of Eibbert, in which they not
only assume generally, with him, that the blood during pregnancy
contains the hormone or stimulating substance for the development
of the mammary gland, but claim to have located the origin of
this substance. They state that the foetus itself produces specific
hormones which stimulate the development of the mammary
gland. They find that repeated injections of extract from the
foetus (a large number, over 100, being employed) lead to develop-
ment of the mammary gland in virgin rabbits. C. Foa (1908)
repeated these experiments, using foetal extract from different
species, particularly bovine, and arrived at the same results. The
hormones which develop the mammary gland are not specific for
the species to which the foetus belongs; their action, as was
noted' by Camus, Gley (1902), and others, is similar to that of
the hormones of the pancreatic and enteric secretion (secretin}.
We cannot, however, admit that these results have the decisive
importance attributed to them in favour of the theory of
chemical co-ordination. Even admitting that extract of foetus,
injected artificially in very large amounts, is able to activate the
development of the mammary gland, we are still far from any
direct proof that the foetus really gives off the supposed specific
hormones to the maternal blood, during physiological pregnancy.
We have already pointed out (p. 90) in regard to the pancreatic
and intestinal secretions that the theory of secretin as a specific
518 PHYSIOLOGY CHAP.
excitant of those glands, and the English authors' theory of
"chemical co-ordination," generally speaking, are ill-founded.
Certain experiments in our own laboratory deserve mention, in
relation to the point we are now discussing, because the method of
experiment lends itself to the solution of this problem. U.
Lombroso in collaboration with Bolaffio employed the method of
parabiosis (supra, p. 102) between virgin and pregnant rabbits.
The animals experimented on only survived at most for nine days ;
but no trace of modification was ever detected in the mammary
gland of virgin rabbits, although the iodine test proved that active
exchanges took place between the two animals. It should be
remembered in judging the negative value of these results in
regard to the hormone problem, that in the virgin rabbit the
mamma is reduced to six or seven simple tubules, and that it ex-
hibits profound modifications even by the third day of pregnancy.
In rats, which longer survive the effects of parabiosis, no
appreciable modifications could be seen in the virgin mamma,
although the time was greatly extended.
An observation of Morpurgo's on a parabiotic couple of mixed
sex supports these negative results. The female became pregnant
after four months' parabiosis, was delivered at term, and suckled
her young, but there was no sign of lactation in the male.
All these observations (while still insufficient) militate not
merely against the theory that the foetus discharges a specific
substance into the maternal blood by which the development of
the mammary gland is stimulated, but, generally speaking, against
the theory that development is activated by any chemical stimulus
circulating in the blood.
XI. The much-debated question of whether the human skin
is capable of absorption must not be omitted from this chapter.
While apparently lending itself to easy solution by experiment,
it is on the contrary a difficult problem, judging from the amount
of literature on the subject, and the contradictory results arrived
at by different workers.
With the exception, as we have seen, of the palms of the hands
and soles of the feet, which have no sebaceous glands, the whole
surface of the body is lubricated with the sebum secreted by
these glands, owing to which the horny layer of the epidermis
is rendered highly impermeable to water even with prolonged
immersion. After a hot bath of 30-60 minutes, the epidermis
of the palm and sole alone is visibly softened, showing that the
skin is unsuited for absorption of water or substances dissolved
in it.
The method of weighing the subject before and after total
immersion in a bath is obviously inadequate evidence for this
statement. In fact, the experiments by this method of Jamin and
De Laures (1872) gave conflicting results ; sometimes there was
ix THE SKIN AND CUTANEOUS GLANDS 519
increase, sometimes decrease, sometimes no variation in weight.
These differences are readily explained by the numerous sources
of error inherent in the method : —
(a) Imperfect sensibility of the balance used for weighing the
subject ; (6) difficulty of avoiding absorption by small accidental
lesions of the epidermis and by the mucous surfaces of the genital
organs ; (c) practical impossibility of estimating the amount of
fluid which is not absorbed but imbibed by the superficial layers
of the epidermis, particularly the skin of the palm and sole, which
is not protected by sebum; (d) impossibility of estimating the
losses from the body during the bath, by respiratory gas-exchanges
and cutaneous transpiration, and by drying after the bath from
the rubbing off of the epidermis.
More probable results, which approximate better with the facts,
are obtained if, instead of weighing, the method of changes in the
volume of the water is adopted, as shown by the displacement of
the level in a capillary tube, communicating with the closed
vessel in which a part only of the body is immersed. Fleischer
(1877) employed the glass cylinder of Mosso's plethysmograph
(which has a capillary manometer), and kept his forearm immersed
in the water for three hours, but found no absorption by the skin.
In order to test whether substances soluble in water were
absorbed by the skin, compounds which could be chemically
detected in small quantities in the urine were employed.
This chemical method is certainly the most delicate and- the
most easily applied in the study of absorption, but integrity of the
epidermis in the part of the body experimented on is essential,
and substances which have an alterative effect on the skin must
be excluded.
The majority of the experiments by this method prove defi-
nitely that when the epidermis is intact it lets through neither
water nor substances dissolved in it, provided the=e really have
no chemical action on the epidermis. Braune (1856), on steeping
his feet in solutions of potassium iodide, potassium iodate, iodic
acid, was unable subsequently to detect iodine in the urine.
Parisot (1863), besides baths of potassium iodide and ferrocyanide
solution, also tried infusions of belladonna, digitalis, and rhubarb,
repeating the experiment twice a day for three to eight days,
without finding any absorption. Hiifner (1880), after soaking his
feet in solution of lithium chloride, looked for lithium without
success in the urine by the spectroscopic method. These negative
results were confirmed by Winternitz (1891), who used aqueous
solutions of 10-15 per cent lithium chloride. Lastly, Fubini and
Pierini (1893) found no absorption by the skin with aqueous
solutions of 3 per cent potassium ferrocyanide, 2 per cent sodium
santonate, 5 per cent sodium salicylate, 5 per cent potassium
iodide, 2 per cent lithium benzoate.
520 PHYSIOLOGY CHAP.
If, instead of aqueous solutions, fluids capable of softening and
dissolving the seburn of the epidermis, e.g. ether and alcohol (not
chloroform which irritates the skin), are employed, a certain
amount of absorption can easily be detected, more with ether
which is a better solvent of fat, less with alcohol which dissolves
fat less easily. Winternitz (1891) demonstrated the presence of
lithium in urine by the spectroscope, after steeping the skin of the
forearm for three and a half hours in an ethereal solution of
lithium chloride, to which a little alcohol had been added ; with
purely alcoholic solutions the results were negative. After
previously smearing the skin with ether, he found a slight
absorption of lithium, after keeping the forearm nine hours in a
watery solution of lithium salts. This experiment proves that it
is the cutaneous sebum which makes the skin refractory to
absorption.
By means of the cataplioretic action of the galvanic current
(also known as electrical endosmosis), it is possible to drive the
aqueous solutions through the skin, and to produce absorption by
the blood and lymph paths (Pascheles, 1895). The amount of
substance absorbed increases with the strength of current, but
beyond a few milliamperes the galvanic current damages the skin.
This method is therefore of little use in therapeutics.
It has often been debated whether volatile substances, e.g.
tincture of iodine, applied to the skin can be absorbed by it. The
positive data of Eohrig are contradicted by the negative results of
Fleischer, who took every precaution to exclude absorption of
iodine by the respiratory passages. Mesnil (1894), on keeping his
arm for thirty-two hours in a glass cylinder filled with iodine
vapour, observed no absorption. On the other hand, Sciolla
(1893), Linossier and Lannois (1894), Guinard and Stoorbe (1894),
obtained absorption of guaiacol when applied to the skin.
Oily substances and unguents applied to the skin are not
absorbed (Baschkis, Obermayer, Fleischer, Fubini and Pierini)
But if the skin be rubbed hard for a long time with thes
unguents, so that they are mechanically pressed into the ha
follicles, gland ducts and intercellular spaces of the epidermis
absorption not only of the dissolved substances but also of
suspended corpuscles can be obtained. From a therapeutic point
of view the most important fact is the absorption of niercuris
salves with friction (Kulzer, Neumann, Fiirbringer, and others).
Voit demonstrated that mercury in the form of metal spherules
can be forced into the human corpse, by energetic rubbing, not
only between the layers of the epidermis, but also into the corium.
But in the living subject, the mercury on coming in contact
with the sodium chloride of the sweat is probably converted into
calomel, and partially into sublimate, and absorbed in that form.
The results of experiments on cutaneous absorption in mammals
ix THE SKIN AND CUTANEOUS GLANDS 521
are conflicting. Generally speaking, it may be said that the
thinner, less horny, an,d more vascular their skin, the better it is
adapted to absorption. Forlanini (1868) succeeded in poisoning
rabbits by simply treating the skin with aqueous solutions of
strychnine acidified with acetic acid. Other workers, however,
obtained negative results on rats and guinea-pigs (Wittich, Fubini
and Pierini).
Signora Traube-Mengarini (1890) made a series of experiments
on the skin of dogs and man by painting the skin of the
abdomen (which is almost hairless) and the mammae with solutions
of borax carmine, of potassium ferrocyanide, and with medicinal
iodine for several days in succession. For human skin, a boy
was painted, once only, between the shoulders with tincture of
iodine. The animals were killed, and a bit of the boy's skin
removed, after 45 minutes, when the solutions applied to the
skin were sought for under the microscope — the carmine being
fixed with sublimate,, the ferrocyanide with ferric chloride (with
which it forms Berlin blue), and fresh sections being made of the
skin treated with iodine by the freezing microtome.
The following results were obtained: (a) the carmine had
only stained the superficial layer of the epidermis ; (&) the
potassium ferrocyanide had penetrated beyond the stratum
corneum into the superficial cells of the stratum granulosum ;
(c) the iodine, on the contrary, had penetrated all the layers of
the epidermis and corium, and had been absorbed by the lymph.
To interpret this penetration of iodine Signora Traube-
Mengarini concluded that it alters the skin chemically by forma-
tion of undefined compounds, particularly with the cutaneous fat.
It is known from previous experiments by Fleischer, Waller, and
Winternitz, that the absorption of various soluble substances, in
solutions of ether or chloroform, takes place more readily and
constantly in the skin of certain mammals than in that of man.
Cataphoresis of soluble substances also occurs more easily in
these animals than in man.
In the skin of frogs the conditions for absorption are still more
favourable, because there is no sebum. It is constantly moist,
and highly vascular. The fact observed by Keid (1890) is interest-
ing to the effect that diffusion through living frog's skin takes
place more easily from without inwards, while in dead skin the
exchanges occur more readily in the opposite direction. This
proves that the absorption of which frog's skin is normally
capable is not a purely osmotic phenomenon, independent of the
vitality of the cells of which it is composed.
According to Pesci and Andres (1901-2), both the living skin
of the frog and that of the higher vertebrates and of man behaves
as a semi-permeable membrane, which permits water to leave
or enter, according to the hyper- or hypo-tonicity of the solutions,
522 PHYSIOLOGY CHAP.
but not the substances which are dissolved in it. The skin of
the frog when altered chemically or by necrobiosis is, on the
contrary, more 'or less permeable to them.
BIBLIOGRAPHY
For the historical literature of the subjects discussed in this chapter, besides
general treatises, see : —
KRAUSE. "Wagner's Handworterbuch d. Phys., art. Haut, 1844.
Analyses of Sweat : —
SCHOTTIN. De sudore, Diss. Leipzig, 1851.
FAVRE. Compt. rend. Acad. d. sc. Paris, 1852.
FUNKE. Moleschott's Untersuch. , 1858.
EAST. Zeitschr. f. phys. Chemie, 1886.
ARGUTINSKY. Pfliiger's Arch., xlvi., 1890.
CAPRANICA. Arch. ital. d. biol., ii., 1882.
SCHIERBECK. Du Bois-Reymond's Arch., 1893.
J. 0. W. BARRAT. Journ. of Physiol., xxi., xxii., xxiv., 1897-99.
W. CAMERER, JTJN. Zeitsch. f. Biol., xxiii., 1901.
E. A. WILLEBRAND. Skandin. Arch. f. Physiol., xiii., 1902.
Innervation of Sweat Glands : —
DUPUY. Journ. de Med., xxxvii., 1816.
MAYER. Tiedemann's Zeitschr. f. Phys., ii., 1826.
AITBERT. Lyon medical, 1874.
GOLTZ. Pfliiger's Arch., xi., 1875.
KENDALL and LUCHSINGER. Pfliiger's Arch., xiii., 1876.
LUCHSINGER. Pfliiger's Arch., xiv., xv., xvi., 1876-77-78.
TRUMPY and LUCHSINGER. Pfliiger's Arch., xviii., 1878.
NAWROCKI. Centralbl. f. d. med. "Wiss., 1879.
OTT. Journ. of Phys., ii., 1879.
LANGLEY. Ibidem, xii. , 1891 ; xvii., 1894.
ARLOING. Arch, de phys. norm, et path., i., ii., 1890-91.
The literature of the Chemical Composition of Milk can be found in all recent
text-books of Chemical Physiology.
For the origin of the Specific Products of Milk and the Influence of Diet, see : —
SSUBOTIN. Virchow's Arch., 1866.
KEMMERICH. Centralbl. f. d. med. Wissensch., 1866.
KUHN. Journ. f. Landwirthsch., 1876.
WEISKE. Ibidem, 1878.
I. MUNK. Arch. f. wissensch. u. prakt. Thierh., 1881.
P. BERT. C. R. de 1'Acad., xcviii., 1884.
A. RIBBERT. Arch. f. Entwickelungsmech., vii., 1898.
R. W. RAUDNITZ. Ergebnisse d. Physiol., ii., Part I., 1903.
R. POPPER. Pfliiger's Arch., cv., 1904.
M. PORCHER. C. R. d. 1'Ac., cxli., 1905.
J. ARNOLD. Munch, med. Wochens., lii., 1905.
STARLING and LANE-CLAYPON. Proc. Roy. Soc., Ixxvii., 1905.
G. PIANTONI. Arch, di farmacol. sper. e sc. aff., vii., 1908.
C. FOA. Arch, di fisiol., v., 1908.
Secretory Process in Cells of the Mammary Gland : —
RAUBER. Uber den Ursprung der Milch. Leipzig, 1879.
PARTSCH. Uber den feineren Bau der Milchdriise. Breslau, 1880.
LANGER. Strieker's Gewebelehre. Leipzig, 1881.
HEIDENHAIN. Hermann's Handb. d. Phys., v., 1883.
THIERFELDER. Pfliiger's Arch., xxxii., 1833.
ix THE SKIN AND CUTANEOUS GLANDS 523
STEINHAUS. Arch. f. Pliys., 1892.
HAMMARSTEX. Zeitschr. f. phys., Chem., xix., 1894.
SZABO. His's Arch. f. Anat., 1896, 352.
Innervation of the Mammary Gland : —
ECKHAED. Beitrage zur Anat. u. Phys., i., 1858.
ROHEIG. Virchow's Arch., Ixvii., 1876.
LAFFONT. Gazette med. de Paris, 1879.
HAMMERBACHER. Pfliiger's Arch., xxxiii., 1884.
VALENTOWICZ. Centralbl. f. Phys., ii., 1888.
MIRONOW. Arch. d. sciences biologiques de St-Petersbourg, iii., 1894.
K. BASCH. Ergebnisse d. Physiol., ii. Part I., 1903.
A. FOGES. Centralblatt f. Physiol., xix., 1905.
S. BAGLIOKI. Zur Analyse der Reflexfunktion. Wiesbaden, 1907.
Cutaneous Absorption : —
BRAUNE. Inaug. Diss. Leipzig, 1856.
WALLER. Proc. Roy. Soc. London, x., 1860.
PARISOT. Compt. rend, de la Soc. de Biol., 1863.
FORLANINI. Ann. univ. d. med. e chir., ccv., 1868.
JAMIN and DE LAURES. Compt. rend, de 1'Acad. d. So., 1872.
FLEISCHER. Inaug. Diss. Erlangen, 1877.
HUFNER. Zeitschr. f. phys. Chem., iv., 1880.
TRAUBE-MENGARIXI. Rendiconti d. R. Ace. dei Lincei, vii., 1890.
REID. Journ. of Physiol., xi., 1890.
WINTERNITZ. Arch. f. exp. Path. d. Pharni., xxviii., 1891.
SCIOLLA. Cronaca d. cl. med. di Genova, 1892-93.
FUBINI and PIERINI. Arch. ital. de biol., xix., 1893.
MESNIL. Centralbl. f. Phys., 1894.
PASCHELES. Arch. f. exp. Path. u. Pharni., xxvi., 1895.
L. PESCI and A. ANDRES. Arch. ital. de biol., xxxv. , xxxvii., 1901-2.
Recent English Literature : —
R. JAMISON and A. F. HERTZ. On the Film or "Skin" of Warmed Milk and of
other Proteid Solutions. Journ. of Physiol., 1901-2, xxvii. 26.
L. F. RETTGEE. The Formation of Film on Heated Milk. Amer. Journ. of
Physiol., 1902, vii. 325.
F. G. BENEDICT. The Cutaneous Excretion of Nitrogenous Material. Journ. of
Biol. Chem., 1905-6, i. 263.
A. W. SIKES. On the Phosphorus and Calcium of Human Milk. Journ. of
Physiol., 1906, xxxiv. 464.
A. W. SIKES. On the Estimation of Proteid in Human Milk. Journ. of Physiol.
1906, xxxiv. 481.
J. H. KASTBE and M. B. PORCH. The Peroxidate Reaction of Milk. Journ. of
Biol. Chem., 1908, iv. 301.
W. TEOTTEE and H. M. DA VIES. Experimental Studies in the Innervation of the
Skin. Journ. of Physiol., 1909, xxxviii. 134.
G. A. OLSON. Milk Proteins. Journ. of Biol. Chem., 1908-9, v. 261.
D. N. PATON and E. P. CATHCART. On the Mode of Production of Lactose in the
Mammary Gland. Journ. of Physiol., 1911, xlii. 179.
INlDEX OF SUBJECTS
Abdominal aortic paraganglion, 45
Abdominal compression, 195
defaecation, 370
micturition, 466
Absorption, 263
action of bile, 212, 220
by bladder, 475
of blood serum, 273
carbohydrates, 271, 274, 299
colloids, 277
crystalloids, 274, 277
cutaneous, 518
epithelial, 266, 331
fat, 269, 278
gastric, 264
an internal secretion, 294
intestinal, 265, 273, 331
passage after, 269
passage after, fat, 270
passage after, protein, 272, 299
passage after, sugar, 271
of poisons, 331
protein, 272, 286, 299
sugar, 271, 284, 299
Accessory adrenals, 47, 50, 53
pancreas, 122
thyroids, 8
Acetone, urine, 402
Acetonuria, 319, 403 «
Acholia, 219
Achroodextrin, 157, 208
Acid, acetic, faeces, 346
acetic, urine, 401
aspartic, tryptic digestion, 211, 384
benzoic, urine, 393
butyric, faeces, 346
butyric, gastric juice, 116
butyric, intestine, 222
butyric, urine, 401
capronic, faeces, 346
capronic, sweat, 492
carbamic, urine, 335, 336, 385
carbonic. See Carbonic
cholalic, bile, 143, 220
cholalic, faeces, 346
choleinic, bile, 143
cyanic, urea, 385
Acid, fatty, sweat, 491
fatty, urine, 401
fellinic, bile, 143
formic, faeces, 346
formic, urine, 401
glycero-phosphoric, bile, 144
glycero-phosphoric, urine, 382
glycocholic, liver, 143
glycuronic, urine, 403
hippuric, urine, 382, 393 '
hydrochloric. See Hydrochloric
indoxyl-sulphuric, 228, 395
isobutyric, faeces, 346
lactic. See Lactic
malic, faeces, 346
ornithuric, 395
oxalic, urine, 382, 400
paralactic, 401
phenaceturic, 395
phenylacetic, 395
phosphoric, urine, 408
propionic, urine, 401
scatoxyl-sulphuric, 228, 395
silicic, urine, 382
succinic, faeces, 346
sulphocyanic, urine, 382
sulphuric. See Sulphuric
taurocholic, bile, 143, 218, 220
uric. See Uric
valerianic, faeces, 346
Acid intoxication, 410
Acromegaly, 41, 42
Addison's disease, 47, 51, 55
Adipogenesis, 322, 330
Adipose tissue, 323
Adonidine, diuretic, 459
Adrenal. See Suprarenal
Adrenaline, 59, 60
Albuminogenesis, 328-30
Albuminuria, 287, 404
haematogenous, 404
physiological, 404
of thyroidectomy, 18
Alcohol, and absorption, 265
and gastric secretion, 265
Alimentary glycosuria, 309
pentosuria, 403
525
526
PHYSIOLOGY
Alimentary protein, 329
Alkaloids, absorption, 331
faeces, 359
urine, 359
Allantoin, urine, 382
Alloxuric. See Purine
Alveoli, secretory, 5
Amidulin, 157, 175
Amino- acids, 211, 212, 221, 288, 293,
384, 387
Ammonia, of blood, 336
of intestine, 336
of liver, 336
origin, 384
of sweat, 491
of urine, 409
Ammonium carbamate, 384, 410
carbonate, 380, 383, 384, 410
cyanate, 382, 386
Amoebae, and proteolytic enzymes, 258
Amphopeptone, 212
Amygdulin, 278
Amylogenesis, 302, 330
Amyloids, digestion of, 179
Amylolytic ferment. See Diastase
Amylopsin, 96, 208, 212
Anabolic processes, 343
Animal gum, 402
starch, 301
Anorexia, 17
Anthrax bacillus, and gastric juice, 180
Anti-diaphoretics, 489
Anti-diastase, 321
Anti-ferments, Ascaridae, 260
Anti-peptone, 211
Antiseptic action, bile, 220
gastric juice, 179
Antitoxicity, adrenals, 50, 55, 56
liver, 331
parathyroids, 35
thyroid, 22, 27
Anuria, auto-intoxication, 338
cholera, 413
and cutaneous secretion, 489
hysterical, 361, 453
Anus preternatural™, 126, 128, 217, 228
Apomorphine, emetic action, 196, 201
Appendices epiploicae, 368
Appendix, vermiform, 365
Arginiue, 384, 392
Aromatic compounds, 393
oxy-acids, urine, 382
Arsenic, renal secretion, 443
Ascaridae, and digestive ferments, 258,
260
Asphyxia, and bile ducts, 216
and glycaemia, 308
Atropine, action on gastric secretion, 109
action on milk secretion, 515
action on salivation, 72
action on sweat, 489, 498
Auerbach's plexus, 198, 233, 246, 247
Auto-digestion, 252-260
Auto-intoxication, 22, 24
Autolytic cleavage products, 406
Azygos nerve, 516
Bacillus mesentericus, 224
Bacteria, action, digestive, 223, 225
action, fermentative, 223, 226
action, putrefactive, 180, 223, 225
chromogenic, of sweat, 492
of faeces, 346
of intestine, 224, 360
of stomach, 179, 180, 223 ; action of
gastric juice on, 180
of urine, 380
Bacterium coli commune, faeces, 346
intestine, 224
Bacterium ureae, 380
Balance, organic, 329
Basedow's disease, 28
Bile, 134, 207, 212
action on alkaloids, 333
action, amylolytic, 209
action, antagonistic to pepsin, 218
action, antiseptic, 220
action, coadjuvant, 221, 281
action, digestive, 217 ; in vitro, 172,
212
action, emulsifying, 212
action on mucous membrane, 284
action, peristaltic, 220
canaliculi, 131
composition of, 143, 144
diastase of, 144
entero-hepatic circulation, 140
enzymes, 144
excretion of, 213
and fat absorption, 281
and fatty acids, 220
fistula, 135
flow, 216 ; innervation, 141, 215
and movements of intestine, 237
origin of, 135, 146, 329
pressure, 142
secretion of, 131, 134, 140, 213
toxicity, 414
Bile acids, 143, 220
ducts, 131, 132, 214 : contractility,
216 ; innervation, 215, 216
pigments, 144, 146, 360, 398
salts, 143, 146, 220
Bilirubin, 144, 346
conversion to urobilinogen, 398
of faeces, 346 ; of liver, 399
Biliverdin, 144, 346
of faeces, 346
Biotoxin, 415
Biuret test, 173
Bladder, 460
absorption in, 475
innervation, 470
nerve centres, 474
sphincters of, 461, 464
structure, 460
INDEX OF SUBJECTS
527
Ulastomycetes, 223, 505 ; and gastric
juice, 258
Blood, ammonia content, 336
caseinogen of, 505
fat content, 322
glycaemia, 308
molecular concentration in uraemia,
414
reaction in digestion, 222
sugar content, 302
in thyroidectomy, 18, 24
Bombyx mori, 313
Bone, digestion of, 178
Bowman's capsule, 419
Bread, digestion of, 178
Bright's disease, 405, 411, 413
" Bronzed skin," 48
Brunner's glands, 122, 124
" Brush border,!' 422, 455
Buccal digestion, 67, 154
Cachexia thyreopriva, 14, 16, 24, 33
Caecal juice, reaction, 366
Caecum, 364
Caffeine, diuretic action, 433, 436, 459
Calabar beans, as scialagogue, 72
Calcium carbonate, urine, 382
metabolism, 355
oxalate, urine, 400
salts, milk, 174
Camphor, 396
Capsule. See Suprarenal
Carbamide, 382
Carbohydrate, absorption, 277, 299
action of bile, 219
action of gastric juice, 174
action of pancreatic juice, 208 ; in
vitro, 213
action of saliva, 157
bacterial fermentation of, 226
digestion, 271
of milk, 505
origin from fat, 313
Carbolic acid, urine, 395
Carbonic acid, 344, 347
cutaneous excretion of, 493
of stomach, 181
of sweat, 493
of urine, 382, 409
Cardia, deglutition, 170
Cardiac glands, 107
Carotid glands, 45
Casein, 174
Caseinogen, absorption of, 287
of blood, 505
of milk, 174, 504, 505
Castoreum, 501
Cataphoresis, 520
Catechol, urine, 395
Cell metabolism, 5, 276, 329, 343
Cells, albuminous, 68, 209
border, 107
centro-acinar, pancreas, 85, 209
Cells, chief, pituitary body, 38 ; stomach,
107, 119
chromaphile, adrenals, 45 ; pituitary
body, 38
epithelial, gastric mucosa, 105
goblet, intestine, 123 ; stomach, 105
mucous, 68
Cellulose, digestion of, 226, 348, 356
and gastric juice, 178
and pancreatic juice, 209
Centres, ano-cortical, 374
ano-spinal, 372
cerebro-spinal, intestinal movements,
252
diabetogenic, 99, 306
genito-spinal, 474
psychical, taste, 110
salivary, 71
spinal, bile duct, 215
vomiting, 202
Centro-acinar cells, pancreas, 85, 209
Cerumen, 501
Cheese, 174
Chemotaxis, 140
Cheyne-Stokes breathing, 17
Chitiii, 179
Chlorides, of urine, 381, 406
Cholaemia, 143, 146
Cholagogues, 136, 139
Cholera bacillus, and gastric juice, 180
Cholesterol, faeces, 346 ; tests, 145, 146
Choline, adrenals, 56
bile, 144
intestine, 348, 360
Chondrin, 179
Chorda tympani, 69, 71, 72
Chromaffine tissue, 38, 44, 45, 53, 60,
61
Chromaphile cells. See Chromaffine
Chromatin, 388
Chromogen, urine, 397
Chromogenic bacteria, sweat, 492
Chyle, 263, 269, 296
Chyme, 170, 194, 207, 213, 216, 231,
363
Chymosin, gastric juice, 118, 174
pancreatic juice, 96
succus entericus,126, 212
Circulus venosus, Haller's, 503
Clotting, 96, 118, 126, 174, 212, 504
Coagulose, 174
Cohnheim's method, ptyalin extraction,
88
Colloids, intestinal absorption, 274, 277
Colon. See Intestine
Colostrum, 509, 512
Compensation products, 328
Conjugated sulphates, 382, 395, 407
492
Copper, in bile, 145
Corpuscles, colostrum, 509
Malpighian, 418
Pacinian, pancreas, 89
528
PHYSIOLOGY
Corpuscles, salivary, 81
Cortex, adrenals,. 44
kidney, 420
Cream, 504
Creatine, muscle, 391
urine, 382, 391, 413 ; synthesis, 392
Creatiuine, sweat, 491
urine, 382, 391, 392, 413
Cresol, urine, 382, 395
Cretinism, 14, 15
Crystalloids, intestinal absorption, 274,
277
Curare, and bile-ducts, 216
a scialagogue, 72
Cutaneous absorption, 518
glands, 485, 498, 502
perspiration, 486
pigment, 482
respiration, 493
Cyanirnide, 392
Cyon's apparatus, 136
Cystine, urine, 382, 408
Daturine, action on cutaneous secretion,
459 ; on salivary, 72
Defaecation, 363
external, 369
inhibition of, 369
internal, 364
mechanism, 368
Degeneration, fatty, 326, 501, 502
keratinous, epithelial, 502
Deglutition, 158, 166
innervation, 167
mechanism, 159
murmur, 162
musculature, 163
radioscopy, 165
reflex, 166
signals, 160
Detnodexfolliculorum, 501
Derma, 480
Detrusor urinae, 461
Dextrin, pancreatic juice, 209
saliva, 157
Dextrose, liver, 303, 314
milk, 505
urine, 317, 402
Deutero-proteose, 211
Diabetes, ammonia content of urine, 410
and cutaneous excretion, 489
Diabetes, experimental, 99, 316, 317
insipid us, 452
mellitus, 314, 316, 402, 433 ; nervous
origin, 321
pancreatic, 99, 103, 317, 322
phloridzin, 316
puncture, 306, 316, 452
suprarenal, 60
Diabetogenic centres, 99, 306
Diaphoretics, 489
Diarrhoea, and cutaneous excretion,
489
Diastase, adrenal, 61 ; of bile, 212 ; of
blood, 305
gastric, 174, 175, 178
hepatic, 304, 321
intestinal, 126, 178, 213
pancreatic, 96, 97, 208
of sweat, 492
of urine, 380, 405
Diastasis recti, 237
Diet, and faeces, 349, 357
and milk secretion, 506
Diffusion, 5, 273, 299
Digestion, 152
accessory, 225
artificial, 170
auto-, 252
buccal, 154
complementary, 225, 227
gastric, 170
intestinal, 207
in vitro, 170, 172, 175, 221
lipolytic, of stomach, 174
natural, 170, 177, 217
post mortem, 252
of protein, 170
salivary, 157
Digitalis, diuretic action, 433
Dimethylketone, urine, 402
Diuretics, 432, 436, 459
Diuretine, 459
Duboisine, action on sweat, 498
Ducts, bile, 132
cystic, 132
galactophorous, 503
hepatic, 132
of Hess, 84, 101
papillary, 422
Santonini's, 84
Stensen's, 83
thoracic, 270
Wharton's, 72, 83
AVirsung's, 84, 87, 98, 269
Duodenum. See Intestine
Dysphagia, 17
Eck's fistula, 335
Eclampsia gravidica, 37
Elastin, 179
Eleidin, 482
Electrical endosmosis, 520
Electrical reaction, muscles of intestine,
238
Emetics, 195, 201
Enterograph, 241
Entero-hepatic circulation, 140
Entero-kinase, 209
Enzymes, amylolytic. See Diastase
chymosin. See Chymosin
diastatic. See Diastase
erepsin. See Erepsin
gastric, 115, 117, 174
glucase, 97
lactase, 127, 213
INDEX OF SUBJECTS
529
Enzymes, intestinal, 126, 212
iuvertive, 126, 213
lipase. See Lipase
lipolytic. See Lipolytie
pancreatic, 96, 208, 221, 319
proteolytic. See Proteolytic
salivary, 81
of mine, 380, 405
Epidermis, 480
Epinephrine, Abel's, 60
Epithelium, functions, absorption, 275
functions, excretion, 358
functions, physiological activity, 274,
436, 437, 510
functions, protection, 259, 331, 358
functions, regeneration, 268, 291
functions, secretion, external, 1, 2,
268, 457
functions, secretion, internal, 268,
437, 457
functions, selection, 331, 352
glandular, 2, 11
intestinal, 123
renal, 455
Erepsin, Cohnheim's, 127, 212, 22] , 228,
293
Erythrodextrin, 157, 175, 208
Esbach's reagent, 18
Eserine, sweat, 498
Esters, glycuronic, urine, 403
Ethereal sulphates, sweat, 492
urine, 382, 395, 407
Evaporation, 487
Excretin, faeces, 346
Excretion, by intestine, 344
by kidney, 377
by skin, 480
Faeces, 344
composition, 346, 356
and diet, 349, 357
in fasting, 351
fat of, 220, 352
in jaundice, 220
nitrogen of, 347, 348, 357
normal, 357
toxicity, 358
Fasting. See Inanition
Fat, 322
absorption, 278, 297
absorption, paths of, 270
action of bile, 220
' action of gastric juice, 118, 178
action of pancreatic juice, 97, 209
action of succus entericus, 126,
213
assimilation, 297, 322
bacterial cleavage, 226
conversion into carbohydrate, 313
of faeces, 220, 352
'intestinal absorption, 297
melting-point, 325
of milk, 504
VOL. II
Fat, origin, alimentary fat, 325 ; carbo-
hydrate, 326 ; protein, 326
putrefaction, 226
storage in tissues, 323
Fatty acids, faeces, 220
sweat, 491
volatile, 401
Fatty degeneration, 326, 501, 502
Fermentation, ammoniacal, urine, 409
gastric, 180
intestinal, 223, 226
Ferratin, 332
Fever, urine, carbonic acid, 409
urine, phosphates, 409
Fibrin, digestion, gastric, 171, 173
digestion, pancreatic, 210
digestion by succus entericus, 126
Fibroin, 179
Filtration, 299
Fistula, Eck's, 335
intestinal, 125, 227
oesophageal, 108
Pawlow's gastric, 108, 112, 114
Schwann's biliary, 135
Thiry-Vella, 125
Food, and bile secretion, 136
digestibility, 179, 349, 358
and faeces, 349
gastro-intestinal digestion, 152, 207
utility value, 349, 358
Frankel's sphygmogenine, 60
thyroid antitoxin, 30
Galactose, 505
Galeotti's method, 11
Gall-bladder, 131, 213
extirpation, 214
fistula, 135
Gases, digestive canal, 348
stomach, 181
Gasteropods, and sulphuric acid, 258
Gastric juice, action, amylolytic, 174
175, 178
action, antiseptic, 179
action, lipolytic, 118, 174
action on mucin, 179
action on nuclein, 179
action on scleroproteins, 179
action, proteolytic, 117, 170, 177
artificial, 154
enzymes, 115, 117, 174
hydrochloric acid, 115, 175, 180
Gelatin, digestive, 354
-peptone, 173
Genito-mammary glands, 512, 516
Genito-urinary glands, 5
Giannuzzi, crescents or demilunes of,
69, 75, 79
Glands, 2
acinous, 67
albuminous, 68
branching, 67
carotid, 45
2 M
530
PHYSIOLOGY
Glands, gastric, 107
genito-mammary, 512, 516
genito-urinaryy5
hepatic, branching, 67
intestinal, 122, 128
Lieberkiihn's, 122
mammary, 502
Meibowmian, 499
mucous, 68
parathyroid, 8
parotid, 67
pituitary, 38
sacral, 45
salivary, 67
sebaceous, 498
serous, 68
sub-lingual, 67
sub-maxillary, 67
sub-orbital, 69
sudiferous, 485
suprarenal, 43
sweat, 485
thyroid, 6
tubular, 67
Glisson's capsule, 132
Glomerulus, kidney, 423, 445
Glucase, 97
Glucose, diuretic action, 433
of liver, 299, 303
of saliva, 157
of urine, 402
Glycaemia, and asphyxia, 308
Glycocoll, 384, 393, 395
Glycogen, 301
estimation, 302
foetal, 310
hepatic, 299, 330
muscular, 310
Glycogenesis, 299-322
in hibernation, 310, 312, 314
Glycolysis, 315, 319-322
Glycosuria, 306, 337, 402, 452
alimentary, 309
pancreatic, 99, 103
suprarenal, 60
of thyroidectomy, 18
Glycuronuria, 403
Gmelin's test, bile pigments, 145, 148,
346
Goitre, excision, 13, 34
Grafts, adrenal, 53
pancreatic, 100
Graminaceae, action of trypsin on, 258
Graves' disease, 28
Gross' method, trypsin, 211
Guanine, urine, 382
Gum, animal, 402
Guthrie's muscle, 461
Haematin, faeces, 287, 345
Haematogen, 332
Haematuria, 405
Haemodromometer, Hiirthle's, 73
Haemoglobin, absorption, 287
Haemoglobinuria, 405
Hair, rate of growth, 483
Halogens, thyroid, 27, 30
Heart, automatic rhythm, 458
Hedin's method, trypsin, 211
Hemipeptone, 211
Henle's loop, 422
Hepatic diastase, 304, 321
Hibernation, glycogenesis in, 310, 312,
314
Histidine, 384
Hormone theory, 90, 111, 129, 142, 300
517
Hydrobilirubin, bile, 144
faeces, 346
urine, 398
Hydrochloric acid, and auto-digestion,
258
action on starch, 175
action on tissues, 258
of gastric juice, 115, 180
Hydrogen, intestine, 348
stomach, 181
Hydruria, 452
Hyoscyamine, 332, 333
Hyperglycaemia, 306, 308, 316. 317,
320
Hyphomycetes, gastric juice, 258
Hypochloruria, 407
Hypophysectomy, 39, 41
Hypophysis. See Pituitary
Hysterical anuria, 361, 453
neurosis, 361
oliguria, 361, 454
Ileum. See Intestine
Inanition, faeces of, 351
and hepatic glycogen, 330
secretion of bile, 138
secretion of succus entericus, 125
Indican, urine, 400 ; sweat, 492
Indigo-blue and -red, 400
-carmine, 438, 513
Indole, faeces, 346
intestine, 228
urine, 400
Indoxyl, intestine, 228
sweat, 492
urine, 400
Insalivation, 156
Internal secretion, 5 ; and absorption,
297
of pituitary, 42
spleen, 121
thyroid, 20, 26
uriniferous tubules, 439
villi, 295, 439
Intestinal acholia, 219
catharsis, 359
Intestine, 122
absorption, large intestine, 269 ; small,
265, 273, 331
INDEX OF SUBJECTS
531
Intestine, bacteria of, 223, 353, 360,
365
caecum, 364
colon, 364
defaecation, 363
digestion in, 213
duodenum, 232, 237, 265
enzymes of, 126, 212, 213
excretion, 344, 354, 358 ; supplement-
ary to kidneys, 360
fermentation, 225
fistula of, 125, 227
glands, 122, 128
ileum, 232 ; functions, 229
innervation, large intestine, 370 ;
small, 233, 247, 370
jejunum, 232, 237, 265 ; functions,
229
juice. See Succus entericus
large intestine, 269, 287, 367
"law" of the, 243
movements of, 231, 234, 240
mucus, 269, 367
musculature, 233
putrefaction in, 225
radiography, 246
reaction, 207, 226, 365
resection, 229
structure, large intestine, 367 ; small,
232
succus entericus, q.v.
valvulae conniventes, 122, 266
villi, 122, 266
Inulin, 315
Invertin, succus entericus, 126, 213
Iodine, cutaneous absorption, 519, 521
of thyroid, 23, 30
Iron, in bile, 145
metabolism, 332, 355
Iscuria, 361
Islets of Langerhans, 86, 102
Jacobson's nerve, 69, 76
Jaundice, 143, 146, 220
Jecorin, 299, 408
Katabolic products, 343, 357
Kefir, 396, 505
Keratin, 174, 483
Kidney, 418
blood-vessels, 422
circulation, 446
cytological changes, 455
external secretion, 425, 439
functions, 410, 432, 442
innervation, reflex, 453
innervation, secretory, 452, 453
innervation, vasomotor, 446
internal secretion, 439, 441, 442,
457
pigment excretion, 457
, structure, 418
uriniferous tubules, 418, 455
Kidney, vicarious action for intestinal
excretion, 360
vicarious action for liver, 338, 414
vicarious action for skin, 493
Kumis, 504
Lact-albumin, 504
Lactase, 127, 213
Lacteal vessels, 263, 269, 297
Lactic acid, faeces, 346
gastric juice, 116
intestine, 222, 348
saliva, 82
urine, 382, 401
Lacto-globulin, 504
Lacto-mucin, 504
Lactose, of milk, 505
of urine, 402
Laevulose, 315, 317
"Law of Intestine," 243
Lecithin, adrenals, 56
faeces, 346
urine, 408
Leguminosae, action of trypsin, 258
Leucaemia splenica, 388
Leucine, 221, 384
Leucocytes, and uric acid, 389
Lieberkuhn's crypts, 122, 125, 363
Lipase, pancreas, 97
succus entericus, 127
Lipolytic ferment, pancreas, 96, 97,
119, 209
stomach, 118, 174
Liver, 130, 300
amylogenesis, 302, 330
anti-diastase, 321
anti-toxic function, 331
bile capillaries, 131
biligenesis, 130
blood-supply, 132, 140, 300
diastase, 304, 321
entero-hepatic circulation, 140
enzymes, 304, 321
exothermal phenomena, 308
of frog, marmot, pigeon, 312
functions, 130, 300, 332
glycogenesis, 300, 330
innervation, 134, 141
secretion, external and internal, 300,
306
in starvation, 330
structure of, 130
urea formation, 335, 383
Lobeline, emetic action, 196, 201
Lumbricidae, and digestive ferments,
258
Lymphagogues, 29
Lymph and chyle, 270
Lymph organs, and protein storage, 330
Lysine, 384
Malpighian acini, 2
corpuscles, 418
532
PHYSIOLOGY
Malpighian layer, skin, 481
pyramids, 420
Maltose, pancreatic juice, 209
saliva, 157
succus entericus, 212, 303
Mammary glands, 502
development in pregnancy, 517
and genital organs, 512
innervation, 512
secretion, 503
structure, 502
Marmot, fat, 314
kidney, 455
liver, 312
Mastication, 155
Meat, in faeces, 356
Meconium, 223, 228, 349
Medulla, adrenal, 44
kidney, 420
Meibowmian glands, 499
Meissner's plexus, 233, 268
Helena, 283
Menopause, 503
Menstruation, 6, 512
Metabolism, of living cells, 5, 276, 329,
343
Methaemoglobinuria, 405
Methane, intestine, 348
stomach, 181
Methods, Bernard-Ore, portal system, 334
Chrzonzsczewsky, sulphindigotate,
438
Cohnheim, ptyalin, 83
Esbach, albumin, 18
Galeotti, thyroid, 11
Gross, trypsin, 211
Hedin, trypsin, 211
Mett, pepsin, 171, 211
Oehl, sulphocyanide, 83
Pfliiger, glycogen, 302
Solera, sulphocyanide, 83
Methyl violet, and protoplasm, 305
Aficrococcus restitucns (Brinck), 292
ureae, 380
Micturition, 464
innervation of, 470
involuntary, 464
and perspiration, 489
voluntary, 466, 468
Milk, action of gastric juice, 118, 174,
178
action of pancreatic juice, 96, 212
action of succus entericus, 126, 212
fat, 175, 504, 509, 511
human, 503 ; composition, 504
influence of diet, 506
influence of nervous system, 512
origin, 510, 512
secretion of, 505, 506 ; mechanism,
508
serum, 505
"witches'," 503
yield of, 506
Milk diet, 338, 352, 358
Milk globules, 504
Milk teeth, 155
Molecular basis of fat, 298
Morgagni's pyramids, 6, 8
Movements, antiperistaltic,- 191, 235
238, 458
of gall-bladder, 216
intestinal, pendular, 234, 241 ; auto-
matic or reflex, 240
intestinal peristaltic, 234, 241
intestinal roll, 235
intestinal vermicular. 234
myogenic, 242
neurogenic, 246
oesophageal, 239
of stomach, peristaltic, 184
of ureter, 458
Mucin, digestibility, 173, 179
of faeces, 367
intestine, 269, 367
saliva, 68, 81
pancreas, 96
thyroid, 29
urine, 402
Mucinogen, saliva, 81
Muscarine, of sweat, 489, 498
Muscle, digestion of, 178
in faeces, 356
Myxoedema, 14
Nephritis and cutaneous excretion,
489
Nervi erigentes, 470
Neurine, adrenals, 55
Nicotine, diaphoretic action, 489, 498
hepatic conversion, 332
Nitrogen, excretion, 329
of intestines, 347, 348
of purines, 389
of urine, 382
Nucleic acids, 388
Nucleins, 388, 408 ; digestibility, 179- .
Nucleo-gluco-protein, 511
Nucleo- proteins, 388
salivary, 81
Nutrition, 152
and milk secretion, 506
Oehl's test, 83
Oesophagus, 154, 158
contractions, 159
co-ordination of movements, 169
deglutition, 158
radioscopy, 165
Oliguria, 361, 454
Oncograph, Roy's, 447
Organotherapy, parathyroid, 33, 37
pituitary, 4*1
spleen, 175
thyroid, 28
Ornithine, 395
Osmosis, 273, 331
INDEX OF SUBJECTS
533
Ov-albumin, 287
Oxaluria, 401
Oxidation, formation of urea, 383
protein, 384, 387
purine, 388
Oxy-acids, aromatic, 382
Oxygen absorption, 347, 389
Pacini's corpuscles, 89
Pancreas, 84
accessory, 122
artificial extract, 98
chemical analysis, 94
centro-acinar cells, 85, 209
corpuscles, 89
diastase, 96, 97, 208
extirpation, 98
glycolytic ferment, 319
grafts, 100
enzymes, 95, 96, 208, 221, 319
innervation, 88
internal secretion, 98, 318, 320
islets of Langerhans, 86, 102
reaction, actual and potential, 94, 207
secretion, 89, 95, 207
steapsine (lipase), 97
structure, 84
trypsin, 96
zymogen granules, 94
Pancreatic diabetes, 98, 318
diastase, 96, 97, 208
digestion, 208 ; in vitro, 221
juice, 89, 95, 207
juice, amylolytic action, 96, 97, 208
juice, lipolytic, 96, 97, 119, 209
juice, proteolytic, 96, 210, 211, 221
Panniculus adiposus, 323
Papain, 174
Papillary ridges, 484
Parabiosis, 102, 518
Paracasein, 174
Paraganglia, 45, 61
Paragangline, Vassale's, 59, 60, 61
Paralytic secretion of milk, 515
of saliva, 74, 129, 318
Parasympathetic body, 45
Parathyroidectomy, 32
Parathyroidine, 37
Parathyroids, 8, 32
functions, antitoxic, 35
functions, supplementary to thyroids,
32, 35
structure, 9
tetany, 36
Parotid gland, 68, 76
saliva, 83
Pawlow's fistula, 108, 112, 114
stomach pouch, 114
Pentoses, urine, 403
Pentosuria, alimentary, 403
Pepsin, 117, 120, 171, 175, 217 ; origin,
120; action of spleen, 121, 125
Pepsin in urine, 405
Pepsinogen, 120
Peptone, 170, 173, 328, 384
absorption, 286
action of pancreatic juice, 211, 384
action of succus entericus (erepsin),
127, 212
formation, stomach, 170, 173
gelatin-, 173
of human milk, 504
reconstitution, 328
Perspiratio insensibilis, 487
sensibilis, 487
Pettenkofer's reaction, bile acids, 145
Pfliiger's glycogen method, 302
Phaeochrome, Poll's, 45
Phenol, faeces, 346
intestine, 227, 228
urine, 395
Phloridzin diabetes, 316
Phosphates, acid, alkaline and earthy,
urine, 408
excretion, fever, 409
Phosphorus, organic compounds, 408
poisoning, 326, 401, 410
urine, 408
Physiological selection, tissues, 331, 352
Physostigmine, diaphoretic, 489
scialagogue, 72
Picrotoxin, sweating, 498
Pigments, bile, 144, 146, 360, 398
cutaneous, 482
Gmelin's test, 145, 346
urinary, 397
Pilocarpine, diaphoretic action, 489, 498
diaphoretic action in anuria, 36
effect on milk secretion, 515
on gastric secretion, 109
a scialagogue, 72
and succus entericus, 126
Pituita, 2
Pituitary body, 38
and acromegaly, 41
extirpation, 39
internal secretion, 42
vicarious function with thyroid, 32, 39
Plastein, 174
Plethysmograph, 446
Plexus, Auerbach's, 193, 233, 246, 247
caeliac, adrenals, 46
caeliac, liver, 141, 307
caeliac, stomach, 198
hypogastric, 248
Meissner's, 233
myenteric, 233, 248
renal, 47
solar, 47, 134
Polypeptides, 331
Polyuria, 452
Potassium indoxyl-sulphate, 400
Precipitine, 294
Pro-ferments, 94
Pro-pepsin, 82, 120
Pro-peptone, 173
534
PHYSIOLOGY
Protein, alimentary, 329
assimilation, 328
cleavage, 211
decomposition, 173, 328
of human milk, 504
regeneration, 289, 292, 328
Proteinogenesis, 328-330
Protein "sparers," 327
Proteolytic ferment, pancreas,96, 210,221
stomach, 117, 170, 177
succus entericus, 126, 212
Proteoses, 173, 328
of gastric digestion, 173
of human milk, 504
Protoplasm, granular structure, 280
plant, 330
Protoproteose, 211
Pro-trypsiu, 82, 96
Psychical excitation, 71, 110
secretion, 109
Ptyalin, 82, 158 ; extraction, 83
Ptyalinogen, 82
Ptyalism, 72
Ptyalogen, 81, 82
Ptomaines, 227, 228
faeces, 359
Puncture diabetes, 306, 316, 452
Purines, 388
endogenous and exogenous, 390
Putrefaction, 223
Pyloric glands, 107
Radioscopy, deglutition, 165
intestine, 246
stomach, 194
Reaction, actual and potential, pancreas,
94, 207
Reactions. See Test
Rectum. See Intestine
Regeneration of protein, 289 ff.
Renal secretion, 418
Rennin. See Chymosin
Restitutive secretions, 263
Retention, bladder, 461
Sacral glands, 45
Saline purgatives, 396
Saliva, 67, 154
composition, 82
diastatic action, 71, 157
extraction, 83
freezing point, 81
mixed, 81
paralytic secretion, 74, 129, 318
parotid, S3
rate of flow, 80
reaction, 81, 158
reflex excitation, 70
secretion, 67, 154
sublingual, 83
submaxillary, 83
Salivary corpuscles, 81
Salivary glands, 67
Salivary glands, albuminous, 68
blood-supply, 73
functional changes, 76
innervation, 69
mucous, 69
selective capacity, 80
Salivatory nucleus, Kohnstamm, 72
Sarcinae, of stomach, 223
Sarcosine, 392
Scatole, faeces, 346
intestine, 227
urine, 395
Scatoxyl, intestine, 238
urine, 238, 395
Schizomycetes , action of trypsin, 258
Schneider's mucosa, 2
Schiitz law, 171, 174, 211
Schwann's fistula, 135
Scialagogues, 72
Scurf, 482
Sebaceous glands, 498
Sebum, 499
Secretin theory, intestine, 90, 129
liver, 142
mammary gland, 517
pancreas, 90
stomach, 111
succus entericus, 129
Secretion, 1 ff.
biliary, 134
cutaneous, 485, 493
external, of liver, 300
gastric, 105, 108, 112 ; inhibition by
fats, 113
internal, 5, 268 ; and external, 268
intestinal. See Succus entericus
lacteal, 502
pancreatic, 89
paralytic, milk, 515
saliva, 74, 129, 315
physiological theory, 4
psychical, 110
leflex, gastric, 109 ; pancreatic, 89 ;
salivary, 71
restitution, 263
renal, 377, 418 ; theory, 426
salivary, 67
urinary, 418
Secretory nerves, 75 ; for milk, 514
renal, 452
for saliva, 75
for sweat, 496
Secretory processes, 1, 72
Sedimentum lacteritium, 387
Selection, physical, by tissues, 276
physiological, intestinal epithelium,
276, 331
Selmi's ptomaines, 359
Serin, thyroidectomy, 18
Serum, milk, 505
Serum, toxicity, thyroidectomy, 24
Serum - albumin, synthesis, 289, 292,
328 ; urine, 405
INDEX OF SUBJECTS
535
Serum-globulin, urine, 405
"Sham feeding," 109, 113, 136
Skin, absorption, 518
glands, 485, 498, 502
innervation, 496
perspiration, 486
respiration, 493
structure, 480
thermo-regulatory functions, 495
vasorriotor action, 495
Smegma preputii, 501
Soaps, 209, 322
Sodium carbonate, succus entericus, 222
chloride, urine, 406
sulphindigotate, 438, 513
Solera's reaction, 83
Sphincters, bile-duct, 214 ; innervation,
215
bladder, 461
rectum, 368 ; anal, 368
Sphygmogenine, 60
Spiny cells, 481, 483
Splanchnics, and bile ducts, 216 ; bile
secretion, 141, 216
and intestine, 247
and kidney, 425, 452
and pancreas, 90
stomach, 198
Spleen, enzymes, 121, 122
extract of, 175
influence on gastric digestion, 175
purines in, 388
and thyroid, functional relations, 31
uric acid in, 388
Splenectomy, 175
Starch, animal, 301
assimilation, 356
conversion, 175, 213
Steapsin, 96, 97, 209, 220
Stercorin, faeces, 346
Stereobilin, faeces, 360, 398
Stomach, absorption, 264
auto-digestion, 252
bacteria, 180, 223
digestion, 177, 179 ; in vitro, 170
enzymes, 115, 117, 170, 174
evacuation, 184
gases, 180
glands, 107
innervation, 108, 197
movements, 184, 204
musculature, 184 ; innervation, 197
Pawlow's, 112, 114
radioscopy, 194
resection, 181
secretion, 108, 119
structure, 105
Strychnine, sweating, 498
Sublingual gland, 68, 72 ; saliva, 83
Submaxillary gland, 68, 72 ; saliva, 83
Substitutive therapeutics, 33
Succus entericus, 125, 212, 221, 292
and bile, 127, 213
Succus entericus, constituents, 126
digestive action, in vitro, 212
digestive action, phvsiological, 221,
268, 282, 286, 353/365
emulsifying action, 126, 212, 222
enzymes, 126, 212, 213
enzymes, chymosin, 126, 212
enzymes, diastase, 126, 213
enzymes, erepsin, 127, 212, 221
enzymes, invertive, 126, 213
enzymes, lactase, 127, 213
enzymes, lipase, 127
enzymes, proteolytic, 126, 127
influence of nervous system, 128
and pancreatic juice, 210
protein content, 292
reaction, 222
Sucking, 110, 155
Suckling, 503, 513
Sugar, absorption, 277, 299
of blood, 175, 213
diuretic action, 433
of milk, 505
origin, 308, 311 ; from fat, 313 ;
glycerol, 314 ; protein, 311
of urine, 402
Sulphates, ethereal, urine, 395, 407
total, urine, 395, 406
Sulphindigotate, sodium, 438, 513
Sulphocyanide, saliva, 82, 83 ; Oehl's
test, 83
urine, 408
Sulphur, urine, 407
Sulphuric acid, intestine, 348, 395
stomach, 181
sweat, conjugated, 492
urine, 381, 395, 407
urine, conjugated, 382, 395, 407
Suprarenals, 43
accessory, 47, 50, 53
antitoxic function, 50, 55, 56
cortical substance, 44, 54
diabetes, 60
double structure, 44, 61
extirpation, 48, 52
extract, 57
functions, 50, 52
grafts, 53
internal secretion, 49
medullary substance, 52
pigment, 55
structure, 44
Suprarenine, 60
Surface tension, urine, 380
Sweat, composition, 490
glands, 485
innervation, 496
molecular concentration, 495
reaction, 490
reflex, 498
secretion, 485
toxicity, 495
Sympathetic nerves, bile-duct, 216
536
PHYSIOLOGY
Sympathetic nerves, bladder, 470
intestine, 247 ; large intestine, 370
liver, 134
pancreas, 88
salivary glands, 69, 73
skin, 496
stomach, 198
thyroid, 8
Synthetic regeneration, protein, 289,
292, 328
Syntonin, 173, 217
Taurine, 408
Teeth, milk, 155
permanent, 155-
Tenesmus, 370
Terpenes, 396
Test, Gmelin, bile pigments, 145, 346
U. Lombroso, cholesterol, 146
Moleschott, cholesterol, 145
Oehl, sulphocyanide, 83
Pettenkofer, bile acids, 145
Solera, sulphocyanide, 83
" Tetania parathyreopriva," 36
" thyreopriva, " 15, 36 •
Tetanus, nicotine, 332
Tetany, 15
Thiry-Vella fistula, 125
Thymic lobules, 11
Thymus, uric acid, 388
Thyreo-gummin, 29
Thyreo-protein, 29
Thyroid gland, 6
accessory, 8
extract, 28
functions, antitoxic, 22, 27
functions, theories, 19
functions, trophic, 33
grafts, 27
internal secretion, 20
iodine of, 23
relations with pituitary, 32, 39
relations with parathyroids, 35
relations with spleen, 31
structure, 6
therapy, 28
Thyroidectomy, 13
albuminuria, 18
birds and reptiles, 19
blood changes, 18
glycosuria, 18
serin, 18
Thyro-iodine, 23, 30
Toxins, alkaloids, 331
mineral, 332
Traube-Hering waves, 448
Trituration, 153
Trypsin, pancreatic juice, 96, 210 ;
extraction, 98
urine, 405
Trypsinogen, 82, 96
Tubercle bacillus, and gastric juice, 180
Tyrosine, 221
Uraemia, 411, 414
Uramino-acids, 385
Urates, 379, 437
acid sodium, 387
neutral, 387
Urea, 334, 343, 360, 382
in bile, 145
diuretic action, 360, 413, 433
non-toxicity, 363, 411
origin, 334-393
in saliva, 80, 82, 361
in sweat, 491
synthesis, 382, 384, 386
in urine, 378, 381, 382
Ureters, 418, 457
automatic rhythm, 458
Urethra, 418
Uric acid, 335, 337, 378, 381, 383, 386
and diet, 390
excretion of, 391
leucocytic theory, 389
non-toxicity, 413
origin, 387-391
secretion, 437
Urinary calculi, 378
casts", 382, 405
Urine, 377
acidity, 222, 379, 408
albuminuria, 404
ammonia of, 409
ammoniacal fermentation, 380
aromatic substances, 393
bacteria, 380
biotoxin, 415
carbamic acid, 335, 336, 385
chromogens, 397
composition, 381
creatinine, 391
enzymes, 380, 405
ethereal sulphates, 395
glycosuria, q.v.
inorganic constituents, 406
molecular concentration, 380
organic acids, 400
pigments, 397
purines, 388
secretion, 418, 425, 455
secretion, mechanism of, 418, 427
secretion, theories of, 426 ff.
sugar of, 402. See also Diabetes
surface tension, 380
toxicity, 24, 334, 360, 410-415
urea, 382
uric acid, 386
Uriuiferous tubules, 421, 455
Urobilin, 397
Urobilinogen, 398
Urochrome, 397
Uroerythrin, 399
Uropoiesis, mechanism, 418, 427
Urotoxia, 411
Urotoxic co-efficient, 411
Utility-value, foods, 349
INDEX OF SUBJECTS
537
Vagus nerve, bile-ducts, 216
intestine, 250
kidneys, 449
liver, 134
pancreas, 90
salivary gland, 70
stomach, 197
Valve, Hochstetter's, 107
ileo-caecal, 364
Valvulae conniventes, Kerkring's, 122,
266
Vasa lactea, 269
Vegetable protoplasm, 330
Vella's loop, 125
Vernix caseosa, 501
Villi, internal secretion, 295
intestinal, 266
Volatile fatty acids, 401
Vomiting, 195
centre for, 202
reflex, 200
Water, excretion of, cutaneous, 344, 487
pulmonary, 344, 487
renal, 344, 432
Wilson's muscle, 461
"Witches' milk," 503
Witte's peptone, 174
Zanthine, 382, 383, 388
bases. See Purine
Zinc, bile, 145
Zymogen, amylolytic, -liver, 304
amylopsin, 197
granules, pancreas, 94
peptic, stomach, 120
INDEX OF AUTHORS
ABDERHALDEN and KONA, glycogenesis,
304, 311
ABEL, carbamic acid, urine, 336
epinephrine, 60
ABELES, urine, sugar, 402
ABELMANN, i'at absorption, 281
pancreas, 101, 289
ABELOUS and LANGLOIS, suprarenals,
50, 53
ACKERMANN, creatinine, 393
ACQUA, bile, 140
ADAMI, secretion of urine, 440
ADDISON, Addisoiis Disease, 47
suprarenals, 47
ADELON, gastric movements, 188
ABLER, eclampsia gravidica, 37
ADRIAN, gastric innervation, 198
ADUCCO, hepatic glycogen, 312
salivary secretion, 80
AFANASIEW, glycogenesis, 307
D'AIUTOLO, accessory thyroids, 8
ALBANESE, neurine, suprarenals, 51, 55
ALBERTONI, bile, 138, 220
diuretics, 433, 434, 436
gastric juice, 113
intestinal absorption, 269, 274
renal circulation, 449
sugars, 433
thyroidectomy, 19
urine, acetone, 402 ; secretion, 432,
433, 436
ALBINI, sweat, 490
ALDEHOFF, diabetes, 319
glycogen, liver and muscle, 310
ALDRICH, adrenaline, 60
ALEXANDER, adrenals, lecithin, 61
ALEZAIS and ARNAUD, adrenals, 51
ALLARA, thyroidectomy, 19
ALMQUIST, bile, 217
ALONZO, thyroidectomy, 24, 26
ALQUIER, parathyroids, 36
ALTMANN, fat absorption, 279, 322
protoplasm, 280
ANDERSON, bladder, 473
intestine, 371
ANDERSSON, suprarenals, 51
ANDREONI, milk, 508
ANDRES, skin absorption, 521
ANSELM, bile, 145
ANSELMINO, sweat, 490
ARAKI, urine, lactic acid, 401
ARCANGELI, villi, intestine, 297
ARCANGELI and CAVAZZA, urobilin, 398
ARDIN-DELTEIL, sweat, 495
ARGUTINSKY, sweat, 490 ; nitrogen con-
tent, 491, 493
ARic6, anuria, 453
ARISTOTLE, bile, 136
bile constituents, 146
ARLOING, deglutition, 166
sebaceous glands, 502
sweat, 495, 497
ARLOING and CHANTRE, defaecation,
372
ARLOING and NICOLAS, toxicity of
faeces, 359
ARNAUD, suprarenals, 51
ARNOLD, milk fat, 512
ARNOZAN, pancreas, 99
ARONSOHN, suprarenal diabetes, 60
ARTHAUD, renal circulation, 449
ASCOLI, precipitine, 294
urea, 387
ASELLI, lacteals, 269
ASHER and CUTTER, salivary secretion,
80
ASP, bile, 141
ATHANASIU, fat derivation, 327
AUBERT, sweat glands, 487, 493, 498
AUERBACH, plexus of, 198, 233, 246
sucking, 155
urine, reaction, 379
AZOULAY, renal secretion, 452
BASER, thyroid, 11
BACCELLI, endovenous injections, 28
spleen, and pepsinogenesis, 121, 176
BAGLIONI, milk, 513
urea, toxicity, 411
BAISCH, urine, animal gum, 402
BALDI, bile, 136
bile circulation, 140
creatinine, 392
digestive reaction of blood, 222
539
540
PHYSIOLOGY
BALDI, intestinal absorption, 282, 287
jaundice, 146
BALDONI, thyroid-, 17
BALFOUR, bile, 135
suprarenals, 44
BALTHAZARD, radioscopy, stomach, 194
v. BAMBERGEU, haematogenous album-
inuria, 404
BARBARA, bile, 136, 139 ; coadjuvant
functions, 221 ; nitrogen content,
147
gastric digestion, 179
gastric secretion, 113
iodides, 23
BARBERA and CYON, thyro-iodine, 23
BARCROFT,saliva, oxygen assimilation, 74
v. BARDELEBEN, thyroidectomy, 16
BARGER, ptomaines, 227
BARISCH, bile, 142
BARRATT, W., sweat, 494
BARTELS, diabetes, 320
BARTHOLIN, liver, 300 ; lacteals, 269
v. BASCH, bile pressure, 142
intestinal movements, 239, 248
BASCHKIS, skin, 520
BASTIANELLI, succus entericus, 127, 213
BATTELLI, adrenaline, 60
BAUER, fat, protein origin, 326 .
protein absorption, 273, 286, 287
BAUMANN, ethereal sulphates, urine,
395, 396
indican, 400
intestinal bacteria, 228
thyro-iodine, 23, 30
urea, 385
BAYLE, vomiting, 195
BAYLISS and STARLING, defaecation,
369
hormone theory, 90, 111
"law of intestine," 243
mechanism of secretion, 90
movements of intestine, 239, 240, 244,
249, 250 ; large intestine, 369
secretiu theory, 90, 111, 129, 142, 517
BEAUMONT, gastric digestion, 154, 170,
179
gastric juice, 117
gastric movements, 185, 188
BEAUNIS, urine, acidity in digestion,
222
BECHTEREW and MISLAWSKI, innerva-
tion of bladder, 474
intestinal movements, 248, 252
BECK, urobilin, 398
BELLATI, liver, antitoxic function, 334
BELLINI, kidney, 418
BENCE-JONES, H., urine, reaction, 379
BENDERSKI, trypsin, urine, 405
BENSEN, thyroidectomy, 26
BERARD, pancreas, 98
BERDACH and PAL, suprarenals, 51
BERENSTEIN, faeces, 353
BERGMANN, uric acid, 378
BERGMAN and HULTGREN, caecal diges-
tion, 366
BERKLEY, Meissner's plexus, 233
renal secretion, 425, 450
BERLATZSKY, caecal digestion, 366
BERLIOZ, urea, 383
BERNARD, CL., amylogenesis, 302
auto-digestion, 254
bile in digestion, 217
gastric secretion, 108, 113, 116
glycogen, 301
glycogenesis, embryonic, 310 ; hepa-
tic, 300, 305 ; muscular, 310 ; from
alimentary protein, 311
hepatic diastase, 304
intestinal movements, 239, 248
kidney, 425
liver, 300
nephrectomy, 410
pancreas, 94, 98
pancreatic juice, reaction, 210
paralytic secretion, 74, 129, 318
puncture diabetes, 60, 316, 322, 452
saliva, 71, 73, 74
salivary glands, 76
steapsin, 97, 210
urine, reaction, 379
urine, secretion, 428
vaso-constrictors, 496
BERNARD-ORE, method of, 334
BERNSTEIN, pancreas, 89
BERRUTI and PEROSINO, suprarenals,
49
BERT, bladder, 471
mammary gland, 508
BERTHELOT, steapsin, 210
BERTHOLD, hair, 483
BERZELIUS, urine, analysis, 378
urine, lactic acid, 401
BETTENCOURT and SERRANO, thyroid
grafts, 27
BETZ, intestinal movements, 239
BEYERICK, lactase, 127
BEZZOLA, intestinal villi, 297
BICHAT, liver, 300
BICKEL, uraemia, 415
BIDDER, bile, intestinal function, 219
renal secretion, 453
stomach, 108, 154, 197
BIDDER and BLUMBERG, deglutition,
167
BIDDER and SCHMIDT, digestion, 154
gastric juice, 108
gastric muscles, 197
intestinal acholia, 219
saliva, 154
BIEDERMANN, saliva, secretory cells, 79
BiEDERMANNandSiNCHOViTz.intestine,
movements, 238
BIEDL, chromafline extract, 61
pancreas, 101
pituitary, 39
suprarenal extract, 57, 58
INDEX OF AUTHOES
541
BILLROTH, thyroid, 15
BIONDI, parathyroids, 11
BIRCHEU, thyroid grafts, 27
BISCHOFF, suprarenals, 43
Bisso, liver, anti-toxic functions, 334
BIZZOZERO, skin, 482
BIZZOZERO and VASSALE, sebaceous
glands, 501
BLEIBTREU, blood, fat content, 322
BLITSTEIN, faeces, 353
BLONDLOT, digestion, 154
gastric movements, 188
BLOT, lactose, urine, 402
BLUM, adrenaline, 60
thyroidectomy, 26
BLUMBERG, deglutition, 167
BOAS, gases of stomach, 181
BOCCARDI, succus entericus, 127
Bocci, gastric juice, 114
urine, toxicity, 411
BOCHEFONTAINE, intestinal movements,
252
salivary secretion, 70
BOECKER, diabetes, 320
BOERHAAVE, digestion, 153
sweat glands, 485
BOERI and REALE, urine, acetone,
402
urine, ammonia, 410
urine, oxalic acid, 401
BOHM, kidney, 421
pancreas, 84
stomach, 119
BOINET, suprarenals, 51
BOLAFFIO, parabiosis, 518
BOLPIREFF, bile, intestinal functions,
218
lipolytic enzyme, 118
succus entericus, 125
BOLL, pancreas, 85
BONFANTI, pepsin, urine, 405
DE BONIS, urine, secretion, 445, 454
BORDAS, intestinal bacteria, 225
BORELLI, digestion, 153
BORISSOW, trypsin, digestion, 211
BORUTTAU, adrenaline, 58, 59
BOSCH, pituitary, 40
BOTTAZZI, adrenaline, 58, 59
erepsin, 127
erythrocytes, 18
thyroid, 18
BOTTAZZI and ONORATO, secretion of
urine, 444
BOUCHARD, faeces, ptomaines, 359
toxicity of faeces, 358, 360, 367
toxicity of urine, 334, 360, 411, 414
urotoxic coefficient, 411
BOUCHARDAT, amylopsin, 97
pancreas, internal function, 98
BOWMAN'S capsules, 436
kidney, 418, 437
physiological theory, urinary secre-
tion, 426, 437, 439
BOYEII and GUINARD, bladder, absorp-
tion, 476
v. BRAAM - HOUCKGEEST, intestinal
movements, 234, 239, 243, 250
stomach, innervation, 198
BRADFORD, urine, secretion, 441, 442
449
BRAND, bile, 138
urine, composition, 378
BRAUN, intestine, 238, 269
BRAUNE, cutaneous absorption, 519
(DI) BRAZZA, thyroid, 11, 31
BRESCHET, sweat glands, 485
BRIEGER, intestinal putrefaction, 227,
228
scatole, faeces, 346
BRINCK, J., protein synthesis, 292
BRINTON, stomach, 188, 198
BROUARDEL, urea formation, 383
BROWN, succus entericus, 213
BROWN -SEQUARD, internal secretion,
49 ; kidneys, 457 ; suprarenals, 44,
48
secretory activity of cells, 1
BRUCKE, absorption, fat, 278, 298 ; pro-
tein, 286, 287
achroodextrin, 157
amino-acids, 293
bile, 217
erythrodextrin, 157, 175
fibrin, 171
gastric juice, 116, 189, 191
glycogen, 302
intestinal villi, 267
pepsin, 117, 172 ; of urine, 405
peptones, 288, 293
saliva, 157
soap, 209
urine, sugar, 402
BRUN, eclampsia gravidica, 37
BRUNNER, glands, 2, 122, 124
pancreas, 98
suprarenals, 55
BRUNO, bile, 210, 216, 218, 219, 226
BUDGE, bladder, innervation, 470, 471,
474
intestinal movements, 250
stomach, innervation, 198
succus entericus, nervous control, 129
BUDGE and MASIUS, ano-spinal centre,
372
BUFALINI, G., bile, 212, 220
salivary glands, 75
BULIGINSKI, ethereal sulphates, 395
phenol, urine, 395
BUNCH, intestine, movements, 241, 248,
250, 252
BUNGE, acid, hippuric, 393
acid, uric, 387
creatine, 392
creatinine, 391
fat, carbohydrate origin, 328
gastric juice, 179
542
PHYSIOLOGY
BUNGE, glycogenesis, 304, 313, 314
haematogen, 332
nitrogen of intestine, 348
saliva, 158
succus entericus, 222
sugar, derivation from fat, 313
thyroid antitoxin, 31
urine, sodium chloride, 406 ; analysis,
381
BURIAN and SCHUR, purine, 390
BURKART, bile in digestion, 217
BURKHARDT, diabetes, 318
BuRTON-OpiTZ, salivary glands, blood-
supply, 73
BUSCH, digestion, 178, 179, 228, 268
intestinal movements, 237
stomach, 188
BUTTE, glycogenesis, 308
renal circulation, 449
CABITTO, sweat, 495
CADEAC and GUINARD, thyroid and
spleen, 31
CADIAT, intestine, 232, 233
liver, 133
CAJAL, RAMON Y, villi, 268
urea, 383
CAMERER, W., urea, 383 ; sweat,
492
CAMUS, enterokinase, foetal hormones,
517
CANALIS, thyroid, 21, 24, 31
CANNON, external defalcation, 369
intestinal movements, 246 ; large
intestine, 369
radioscopy of stomach, 194
CANNON and DAY, salivary secretion,
157
CANNON and MOSER, deglutition, 165
CANTANI, pancreas, 98
CAPITAN, physiological albuminuria,
404 ; sweat, 495
CAPOBIANCO, parathyroid, 12, 33
CAPPARELLI, diabetes, 320
erepsin, 293
pancreas, 99, 101
peptones, 293
CAPRANICA, sweat, creatinine, 491
CARBONE, adrenals, neurine, 56
CARDANO, mammary gland, 503
CARRIERE, anuria, 453
CARVALLO, intestinal movements, 247
CARVALLO and PACHON, digestion,
181
CASCIANI, ethereal sulphates, 396
CASELLI, pituitary, 39, 40
CASH, intestinal absorption, 279
lipolytic enzyme, 118, 174
CASSAN, suprarenals, 47
CAVAZZA, urobilin, 398
GAVAZZANI, E., bile, 141
glycogenesis, 304, 305, 307, 311
glycosuria, 317
CAVAZZANI, E., urinary secretion,
diuresis, 434
CAVAZZANI, A. and E., diabetes, pan-
creatic, 318
diabetogenic centres, 99
hepatic glycogenesis, 307
CELLI, intestinal bacteria, 224
CENTANNI, pituitary, 40
thyroidectomy, 18
CERLETTI, pituitary, 42
CHANTRE, anal sphincter, 372
CHARCOT, liysterical anuria, 361
CHARRIN, sweat, 495
CHAUVEAU, anal sphincter, 373
glycogenesis, 313
CHIRAC, vomiting, 195
CHITTENDEN, digestion, 174, 210
glycogenesis, 303
CHITTENDEN and LAMBERT, hepatic
glycogenesis, 303
CHLAPOWSKI, salivary centres, 71
CHOSSAT, bile, 138
CHRZONSZCZEYVSKY, method of, 438
CHVOSTEK, parathyroids, 37
CIECHOWSKY, intestinal bacteria, 224
CLEMM, salivary digestion, 157
CLTJZET, urine, surface tension, 380
COGGI, ethereal sulphates, 396
COHNHEIM, auto-digestion, 254
bile, 141
bladder, absorption, 476
diabetes, glycolytic ferments, 319
diastase, urine, 405
erepsin, 127, 293
gastric glands, 110, 122
intestinal absorption, 245, 275, 276,
293
intestinal movements, 245
saliva, 83
COLASANTI, toxicity of urine, 414
uric acid, 386
COLASANTI and BONANNI, diabetes,
320
COLASANTI and MOSCATELLI, lactic acid,
urine, 401
COLBERG, bladder, 462
COLIN, caecum, 365
glycogenesis, 301
pancreas, 91, 98
saliva, 158
vermicular movements, 234, 243
COLLINA, acromegaly, 41
COLZI, thyroidectomy, 19, 20, 24
COMTE, pituitary, 40
CONNSTEIN, lipolytic ferment, 174
CONTEJEAN, auto-digestion, 256
lipolytic enzymes, 118
CONVERS, stomach, 198
CORANDA, ammonia, urine, 410
CORONA, saliva, 158
CORONEDI, thyroidectomv, albuminuria,
18
thyroidectomy, and kidneys, 26
INDEX OF AUTHOES
543
CORONEDI, thyroidectomy, and spleen,
31
CORONEDI and LTJZZATO, tliyroidectomy,
reaction of urine, 18
CORONEDI and MAIICHETTI, thyroid-
ectomy, halogens, 30
myxoedema, 18
COURTADE and GUYON, bladder, in-
nervation, 473
defaecation, 371, 372
intestinal movements, 249
CRACIUNO, bile, 145
CREMER, fat, protein origin, 327
glycosuria, 314
CRISTIANI, A., suprarenals, 52
thyroidectomy, reptiles, 19 ; grafts, 28
CRISTIANI, H., suprarenals, 52
CROFTON, adrenal diabetes, 60
adrenals, lecithin, 61
CRUIKSHANK, urine, composition, 378
CUMMINS, trypsin, 210
CURLING, goitre, 15
CUTTER, salivary secretion, 80
CYBULSKI, suprarenals, 56, 58
CYON, holder, 136
pituitary, 40, 41
thyro-iodine, 23
thyroid, 23, 27
CZATARY, albuminuria, 405
CZERMAK, saliva, 74, 75
CZERNY, gastrotomy, 170, 181
intestinal absorption, 269, 287
CZYHLARZ and MARBURG, vesical in-
ner vation, 474
DALE, pancreas, 86
DALE and BARGER, alkaloids, 227
DALLA VEDOVA, pituitary, 40
DALLEMAGNE, intestinal bacteria, 225
DALTON, glycogenesis, 302
DANILEWSKY, digestion, 174
DASTRE, bile, iron content, 145
pituitary, 39
DEBEYRE, zymogen, 94
DECAISNE, human milk, 507
v. DEEN, hepatic glycogen, 313
DEGANELLO, gastrotomy, 182
DEHN, urine, sodium chloride, 406
DELEZENNE, succus entericus, 126, 129
DELL' ACQUA, bile, entero-hepatic cir-
culation, 140
DELPRAT, glycogenesis, 303
DEMJANENKO, intestinal villi, 297
DIAKONOW, protein absorption, 286
DIAMARE, pancreas, 87
suprarenals, 44, 45
DOBBERT, stomach, 198
DODART, perspiration, 487
DOGIEL, human milk, 504
pancreas, 86
DOHRN, pancreas, 101
DE DOMINICIS, diabetes, experimental, 99
diabetes, pancreatic, 317, 318
DE DOMINICIS, intestinal bacteria, 225
pancreas, 99, 101, 104
DONDERS, stomach, 197
DORELLO, stomach, innervation, 197
DOYON, sphincter of bile-duct, 216
DRAGO, intestinal villi, 297
DRECHSEL, carbamic acid, urine, 335-
336
urea formation, 335, 385
DRESER, urine, molecular concentration,
380, 435
DREYFUS, intestinal bacteria, 225
DUCCESCHI, defaecation, 374
stomach, movements, 186, 189, 191,
193, 197
thyroidectomy, plasma, 18
vomiting, 204
DUFOUR, asphyxia, 308
DUKES, albuminuria, physiological,
404
DUMAS, nephrectomy, 410
DUPUY, sweat, 496
DUTROCHET, diffusion, 5, 273
DUTTO, suprarenals, 55
thyroidectomy, 24, 25
DYALL, bile, 140
DZONDI, vomiting, 197
EBERLE, digestion, 154
gastric juice, 117
stomach, 188
v. EBNER, pancreas, 85, 87
EBSTEIN, diabetes, 452
pepsin, 117
pro-pepsin, 120
stomach, 119
ECK, fistula, 335
ECKER, A., suprarenals, 43
ECKHARD, glycosuria, 306
hydruria, 452
intestinal movements, 237
nervi erigentes, 371, 470
salivary centres, 71
salivary secretion, 73, 83
secretion of milk, 514
secretion of urine, 428
EDKINS, gastric juice, 111
EDMUNDS, parathyroidectomy, 33
EDWARDS, W. F., sweat glands, 487
EHRENTHAL, faeces, 353
EHRMANN, intestinal movements, 249
EICHHORN, sweat glands, 485
EICHHORST, protein absorption, 287
EIMER, intestinal absorption, 279
v. EISELSBERG, thyroidectomy, 15 ;
grafts, 27, 28
ELLENBERGER, caecal digestion, 366
saliva, 158
ELLIOTT, adrenaline, 58, 59
EMICH, bile, 218
EMMINGHAUS, salivary secretion, 70
ENDERLEN, intestinal peristalsis, 236
ENGEL, urobilin, 399
544
PHYSIOLOGY
EXGELMANN, cardiac rhythm, 242
intestinal movements, 235, 238,
250
EKDHEIM, eclampsia gravidica, 37
parathyroids, 36
ERNEST, bile, 220
D'EKRICO, intestinal absorption, 271
ESBACH, albumin, 18
ESCHERICH, intestinal bacteria, 223,
224
D'EVANT, renal secretion, 452
EVVALD, anal sphincters, 372
bladder, 475
fat absorption, 279
intestinal fistula, 269
secretory nerves, 453
thyroidectomy, 19
urine, ethereal sulphates, 396 ; fever,
C02 in, 409
EXNER, intestinal movements, 233,
244
EYKMAX, deglutition, 166
FAGGE, ureters, 459
FALCK, urine, excretion of water, 432
FALK, deglutition, 159, 163
gastric juice, 180
FALKENBERG, thyroidectomy, glycos-
uria, 18
FALLOISE, bile, 142
FANO, cardiac rhythm, 242
gastric movements, 204
peptone, 289, 290, 291
thyroid, 23, 31
FAXO and ZANDER, thyroid, antitoxic
functions, 24
FARKAS, pancreatic juice, 95
FASOLA, bladder, 476
FASOLA and SABBATANI, intestine,
movements, 235
FAVRE, sweat, 490
FEDELI and CASCIANI, ethereal sulph-
ates, urine, 396
FEHR, saliva, 158
FELZ and RITTER, urine, toxicity,
411
FERBER, urine, secretion, 432
FERMI, auto-digestion, 258
Bacterium coli, 224, 225
digestibility of foods, 179
gastric juice, action on bacteria,
180
FIBINI, intestine, movements, 235
FICHERA, pituitary, 41, 42
FICK, A., absorption, peptone, 288,
293
kidney, 440
FIGDIER, hepatic glycogenesis, 301
FILETI, thyroid, 31
DE FILIPPI, digestion, 182
intestinal resection, 230
liver, antitoxic function, 337
FIORENTINO, mammary gland, 503
FISCHER, E., glycogenesis, 314
lactase, 127
polypeptides, 331
purines, 388
uric acid, 388
FLECKSEDER, pancreas, 101, 282
FLEIG, bile, 142
FLEISCHER, cutaneous absorption, 519,
520, 521
iodine, 520
v. FLEISCHL, bile absorption, 143, 148
FLEISCHMANN, milk, 506
FLETCHER, saliva, 80
FLINT, stercorin, 346
FOA, C., foetal hormones, 517
digestion, reactions, 207-208
succus entericus, 222
FOA and ANDREONI, milk, 508
FOGES, genito-mammary relations, 517
FORLANINI, cutaneous absorption, 521
FORMANEK, uric acid, 388
FORNIER, kidney, 422
FORSCHBACH, parabiosis, 101
FOSTER, M., absorption, fat, 270, 298
absorption, protein, 272
defaecation, 374
diffusion, 276
glycogen, hibernation, 311
skin, C02 excretion, 493
FOURCROY and VATJQUELIN, urine,
composition, 378
Fox, thyrotherapy, 28
FRANCOIS - FKANCK, intestinal nerves,
370, 371
sweat, 490
FRANK, O., fat absorption, 284
FRANKEL, kidney, internal secretion,
455 ; sphygmogenine, 60
thyroid antitoxin, 29
FiiANKL-HocHWART, defaecation, 372,
375
FRANSEX, stomach, 298
FREDERICQ, lymph organs, fasting, 330
FRENKEL and CLUZET, urine, surface
tension, 380
FRERICHS, diabetes, 314
digestion, 154, 178
glycogen, 310
jaundice, 147
oxalates, 401
pancreas, 98
saliva, 82
uric acid, 387
urine, secretion, 429
v. FREY, pancreas, 85
saliva, 74
suprarenals, 43
zymogen, 94
FREIDEMANN, pituitary, 40
FRIEDEXTHAL, intestinal absorption,
271
urine, reaction, 379
FRIEDLANDER, bile, 142
INDEX OF AUTHOES
545
FRIEDMANN, bladder, innervation, 474
FROHLICH, defaecation, 375
FROUIN, gastric juice, 111, 113
succus entericus, 125, 129
FUBINI and PIERINI, cutaneous absorp-
tion, 519, 620, 521
FUHR, thyroid, 23
FUNKE, skin, 483
sweat, 490
FURBRINGER, albuminuria, physiologi-
cal, 404
cutaneous absorption, 520
ethereal sulphates, 407
oxalic acid, 400
sulphuric acid, 407
v. FURTH, suprarenine, 60
FUSARI, parathyroids, 11
suprarenals, 44
GABBI, albuminuria, 404
GAGLIO, auto-digestion, 254
bile, 222
compression of aorta, 372
diabetes, pancreatic, 318
oxalic acid, urine, 401
pituitary, 40, 41
GALEN, bile, 136
bile constituents, 146
GALEOTTI, secretion of urine, 435, 443,
454
thyroid and parathyroid, 11
GALEOTTI and FASOLA, bladder, mucous
membrane, 476
GALLI, bile, 138
GALLOIS, uraemia, 411
GARROD, bilirubin, 398
urobilin, 397
urochrome, 397
GASKELL, cardiac rhythm, 242
GASPARDI, auto-digestion, spleen, 256
GATTA, pituitary, 39
GAUDENZ, alimentary bolus, 156
saliva, 158
GEHRING, urine, enzymes, 405
GEMELLI, pituitary, 42
GENERALI, parathyroids, 10, 32
GERHARDT, pancreatic diabetes, 321
salivary glands, section of nerves,
76
GERLACH, protein absorption, 288
GEROTA, bladder, mucous membrane,
476
GESSNER, intestinal bacteria, 224
GIACOMINI, suprarenals, 44, 54
GIACOSA, uric acid, 388
GIANNELLI, pancreas, 85, 87
GIANNUZZI, bile, 212, 220
bladder, innervation, 474
demilunes, 69, 75
saliva, 75
vomiting, 195
GIBBES, kidney, 455
pancreas, 87
VOL. II
GILBER, intestinal bacteria, 225
GILLESPIE, succus entericus, 207
GIOFFREDI, adrenal extract, 58
GINSBERG, intestinal absorption, 272
GIRARD, glycogenesis, 303
GLEY, foetal hormones, 517
glycosuria, thyroidectomy, 18
pancreas, 101
parathyroids, 11, 32, 35
pituitary, 39, 40
sweat, 495
thyroidectomy, 17, 19, 24, 28
urine, reaction, 379
GLEY and LAMBLING, bile, 220
GLISSON, glands, 2
jaundice, 146
GLUGE, defaecation, 373
GLUZINSKI, digestion, 177
GMELIN, bile pigments, 145
caecum. 365
digestion, 154
liver, 300
GODARD and SLOSSE, thyroid juice,
29
GOLDMANN, thyro-iodine, 30
GOLL, urine, secretion, 427
GOLTZ, bladder, innervation, 474
defaecation, 372, 373, 374
stomach, innervation, 198
sweat, 496
GOLTZ and EWALD, bladder, innerva-
tion, 475
defaecation, 372
urine, secretion, 453
GORINI, kefir and kumis, 505
GORUP - BESANEZ, oxalic acid, urine,
401
uric acid, 386
GOTTLIEB, bile, 145
pancreas, 89
suprarenal extract, 57, 58
thyro-iodine, 30
GRAHAM, crystalloids, 274
GRATIOLET, suprarenals, 49
GREENWOOD, gastric secretion, 117
GRIFFITHS, bladder, innervation, 470 ;
bladder, sphincters, 461
GRIJNS, urine, 426
GROBER, saliva, sulphocyanide, 82
GROCCO, creatinine, 391, 393
GROSS, trypsin, 211
GRUTZNER, Brunner's glands, 124
pancreatic enzymes, 97, 209
pepsin, 117, 172
pro-pepsin, 120
salivary centres, 71
urinary secretion, 428, 433
GUARNIERI, neurine, adrenals, 55
GUEHRINI, pituitary, 41
GUINARD, absorption, cutaneous, 520
absorption, thyroid, 31
absorption, vesical, 476
GULL, myxoedema, 14
2N
546
PHYSIOLOGY
GURTL, sweat glands, 485, 486
GURWITSCH, renal secretion, pigment,
457
GUTEMAXX, pancreas, 103
GUYOX, bladder, 47
intestinal movements, 246, 249, 371
thyroid, 20
HAESER, mammary gland, 503
urine, specific gravity, 379
HAHX, liver, antitoxic functions, 335
urea, 385
HALBAN and KNAUER, genito-mammary
relations, 516
v. HALLER, bladder, sphincters, 463
circulus venosus, 503
deglutition, 159
glands, 2
stomach, 185
vermicular movements, 234
HALLERVORDEN, ammonia, urine, 410
HALLIBURTON, choline, 360
faeces, 346
pancreatic juice, 96
urine, 382
HAMBURGER, bile, 145
biological reaction, 299
fat absorption, 298
intestinal absorption, 274
precipitine, 294
HAMMARSTEX, albuminuria, 405
bile, 144, 217
clotting, 174
gastric juice, 118, 218
gastric juice, pepsin, 117
mammary glands, 511
saliva, nucleo-protein, 81
HAMMERBACHER, milk, 515
saliva, analysis, 82
HANC, micturition, 46
HANSEMANN, pancreas, 87, 103
HARLEY, VAUGHAN, absorption, in-
testine, 269
absorption, pancreas, 282
bile, 143, 148
urobilinogen, 398
HARNACK, sweat, 490
HAWKINS, albuminuria, 404
HAYEM, urobilin, 399
HEDIX, trypsin digestion, 211, 384
urine, arginine, 384
HEDON, diabetes, 318
pancreas, 99, 100, 104
H£DON and VILLE, fat absorption, 282,
283
HEGER, thyroid juice, 29 ; liver, anti-
toxic functions, 332
HEIDEXHAIN, bile, 136, 141, 142
bladder, sphincters, 462
diuresis, 434
faeces, 353
gastric juice, 116
gastric glands, 110, 117, 119
HEIDEXHAIX, intestinal absorption. 274,
279 ; fat, 298
intestinal villi, 268
lymphagogues, 29
mammary gland, 510, 513, 514
milk, 509
pancreas, 85, 89, 92, 97
saliva, paralytic secretion, 75
salivary glands, 76
secretion, 4
secretory cells, salivary, 68, 76,
78
secretory fibres, chorda, 75
stomach, 105, 119
thyroid, 1]
trypsin-zymogen, 96
urinary secretion, 429, 431, 433.
438
zymogen, 94
HEIXZ, gastric juice, 118
HELLIN and SPIRO, kidney, functions,
443
v. HELMONT, urine, composition, 378
HEMMKTER, intestine, reaction, 207 ;
succus entericus, 207
HEXLE, kidney, 420
secretions, 4
zymogen, 94
HEXXEBERG, intestinal gases, 348
HENRI, bile, 142
saliva, 71
HENSCHEX, urinary secretion, 438
saliva, latent period, 73
HENSEX, hepatic diastase, 304
glycogen, 301
HERING, salivary secretion, 73
HERMAXN, faeces, formation, 352,
353
protein absorption, 286
protein absorption, theory
succus entericus, 213
urine, secretion, 428, 430
HEROX, succus entericus, 213
HERTER, diabetes, adrenal, 60
HERXHEIMER, pancreas, 103
HERZ, sucking, 155
HERZEX, intestine, 228
thyroid ectomy, albuminuria, 18
HERZOG, pancreas, 103
HESS, intestinal absorption, 282
lactic acid, urine, 401
pancreatic ducts, 84, 101
HESSE, glycogenesis, 304, 311
peristaltic movements, 236
HICQUET, tetany, 15
HILDEBRAND, thyro-iodine, 30
HILLEL-JAFE, intestinal movements,
238
HIRSCH, stomach. 188
HIRT, Brunner's glands, 124
HLASKO, vomiting, 198, 202
HOBER, intestinal absorption, 276
pigment excretion, kidney, 457
INDEX OF AUTHOKS
HOBER, urine, reaction, 380
HOCHSTETTER, stomach, 107
HOFFMANN, albuminuria, 405
creatinine, 391
gastrotomy, 182
pancreatic juice, 209
urine, diastatic enzyme, 405
urine, pepsin, 405
HOFMANN, C. S., intestinal gases,
348
HOFMANN, FR., fat absorption, 323
uric acid, 370
urine, acidity, 379
HOFMEISTER, caecum, 366
cyanic acid, 386
fat absorption, 298
glycosuria, 309
intestinal absorption, protein, 289
lactose, milk, 508
lactose, urine, 402
milk, human, 504, 508
peptone, 289, 290, 291
parathyroids, 32
pituitary, 39
saliva, 158
thyroidectomy, 26
thyro-iodine, 30
urea, formation, 386
HOFMEISTER and SCHUTZ, gastric move-
ments, 185, 197
urea, 386
HOGYES, sweat, 498
HOPKINS, bilirubin, 398
HOPPE-SEYLER, albuminuria, 405
aromatic compounds, 395
ethereal sulphates, 395, 396
faeces, 346
intestinal absorption, 273
intestinal gases, 348
saliva, 82
urine, 382
urea formation, 385
HORBACZEWSKI, uric acid, 388
HORNBORG, gastric glands, 110
HORSLEY, pituitary, 39
thyroidectomy, monkeys, 19
thyroid grafts, 27
HORTON-SMITH, intestinal absorption
(protein), 288
peptone diet, 288
HORWATH, intestinal movements, 239
HOWELL, pituitary, 41 .
HOWITZ, thyro-therapy, 28
HUBER, ov-albumin, 287
HUFNER, cutaneous absorption, 519
intestinal putrefaction, 226
HULTGREN, caecum, 366
suprarenals, 51
V. HUMBOLDT, mammary glands, 503
HUNTER, auto-digestion, 252, 260
liver, 300
HUPPERT, albuminuria, 404
HUSCHKE, kidneys, 418
INZANI and LUSSANA, auto-digestion,
254
IRSAI, thyro-iodine, 30
JACOBI, movements of intestine, 248, 250
JACQUES, liver, antitoxic functions, 332
JACUBOWITSCH, saliva, sulphocyanide,
82
JAFFE, indican, 400
• ornithine, 394
uric acid, 387
urobilin, 398
v. JAKSCH, urine, acetone, 402
urine, volatile fatty acids, 401
JAKOTSKY, pancreas, 87
JAKOWSKI, intestinal bacteria, 228
JAMIN and DELAURES, cutaneous absorp-
tion, 518
JAPPELLI, lipase, 127
succus entericus, 127
JASTROWITZ, pentosuria, 403
JAWORSKI, intestinal bacteria, 224
stomach, 177
JENSEN, intestinal bacteria, 224
JOBERT, anuria, 453
JOHNSON, albuminuria, 404
creatinine, 391
JOLYET, internal defaecation, 364
JULLIARD, thyroidectomy, 14
KAHN, deglutition, 166, 167
KAISER, eclampsia gravidica, 37
gastrotomy, 170, 181
KARAKASCHEFF, pancreas, 103
KAST, sweat, 491, 492
KATZ and WiNKLER,ileocaecal valve, 371
KAUDERS, intestine, movements, 235
KAUFMANN, pancreas and diabetes, 99,
319
KAULISCH, acetone, urine, 402
KAUPP, absorption, bladder, 476
KEHRER, bladder, 471
KENDALL and LUCHSINGER, sweat, 496
KERKRING, valvulae conniventes, 122,
256
v. KERMAUNER, faeces, 355, 356
KEUCHEL, salivary inhibition, 72, 75
KHIZHIN, gastric juice, 111, 113
KIENER, urobilin, 399
KINDERMANN, deglutition, 166
KING, thyroid, 11
KIRSTEIN, peristaltic movements, 235
KLECKI, intestinal bacteria, 225
KLEIN, suprarenals, 47
KLEMENSIEWICZ, pepsin, 117
KLUG, succus entericus, 127, 128
KNAUER, genito-mammary glands, 516
v. KNAUT, stomach innervation, 198
KNIERIEM, urea, 384
uric acid, 387
KOBNER, jaundice, 146
KOCH, gastric juice, action on cholera
bacillus, 180
548
PHYSIOLOGY
KOCHER, goitre, 13, 14, 15
intestine, 230 .
thyroid, 13, 14, 19, 20, 27
KOCHS, ethereal sulphates, urine, 396
hippuric acid, 394
KOHLRAUSCH, micturition, 464, 469
thyroid, 11
KOHN, suprarenals, 44, 45, 53, 54
KOHNSTAMM, salivatory nucleus, 72
v. KOLLIKER, intestinal absorption,
279
secretion, 4
zymogen, 94
KONIG, milk, lactose, 505
KONIGSBERG, kidney, pigment excre-
tion, 457
KORECK, intestine, 128
KOROWIN, pancreas, 97
KOSSEL, nucleoproteins, 388
purines, 388
KRATSCHMEK, glycogenesis, 303
KRAUSE, intestinal villi, 266
pancreas, 84
sweat-glands, 486
KREHL, fat absorption, 279
KREIDL, pituitary, 39
KRETSCHY, gastric juice, 116
KRIMER, urine, secretion, 428
KROLOW, Brunner's glands, 124
KRONECKER, deglutition, 159, 163
heart, 193
hippuric acid, 394
KRONECKER and LUSCHER, deglutition,
168
KRONECKER and MELTZER, deglutition,
168
KRUGER, saliva, 82
KRUGER and WULFF, nitrogen of pur-
ines, 389
uric acid, origin, 389
KRUKENBERG, chromogen, suprarenals,
55
KRUSE, kidney, 455
KUDREWETZSKY, pancreas, 90
KUHN, gases of stomach, 181
milk secretion, 507
KUHNE, antipeptone, 11
bile, 212
digestion, 173
erepsin, 221
fat absorption, 325
hemipeptone, 212
intestinal bacteria, 226
leucine, 211
pancreas, 86, 91, 93, 210
peptone, 173, 289, 293
proteolysis, 174, 221, 384
stomach, 188
trypsin, 96, 97, 211
urea, 384
KUHNE and CHITTENDEX, proteolysis,
174
KUHNE and LEA, pancreas, 91, 93
KUHNE and POLLITZER, peptone, 290
KULZ, amylolytic enzyme, liver, 305
diabetes, 314
glycogen, liver and muscle, 310
glycogen, protein origin, 311, 312
glycosuria, 306
KULZ and ALDEHOFF, hepatic glycogeu,
310
KULZER, cutaneous absorption, 520
KUMAGAWA, fat, protein origin, 327
KUMAGAWA and SUTO, intestinal absorp-
tion, 271
KUNDE, jaundice, 146
KUNKEL, bile, 145 ; nitrogen content^
147
urine, 378
KIIPFFER, C., liver, 132
movements of intestine, 248, 250
KURAJEW, coagulose, 174
KUSSMAUL, stomach, 188
KUTSCHER, trypsin, 127
LAFFONT, milk secretion, 515
LAGUESSE, pancreas, 85, 87, 102
zymogen, 94
LAMBERT, glycogenesis, 303
LAMBLING, bile, 220
LANDAU, suprarenals, 53
LANDMEYER, pancreas, 289
LANDOIS, albuminuria, 404
bile, 138
jaundice, 147
salivary secretion, 70
LANDWEHR, animal gum, urine, 402
pancreas, 226
LANE-CLAYPON and STARLING, mam-
mary gland, 517
LANGE, eclampsia gravidica, 37
sweat, carbonic acid, 493
LANGENDORFF, pancreatic juice, 209
pepsin, 117
thyroid and parathyroid cells, 7, llr
12
LANGERHANS, centro-acinar cells, 85
islets, 86
stratum granulosum, 482
LANGLEY, adrenal extract, 58, 59
gastric cells, 120
hepatic glycogen, 312
propepsin, 121
rate of secretion, 80
saliva, 75
secretory cells, 79
sweat, 497
LANGLEY and ANDERSON, bladder in-
nervation, 473
defaecation, 371
LANGLEY and FLETCHER, rate of salivary-
secretion, 80
LANGLOIS, adrenaline, metabolism, 62
chromaffine extract, 61
suprarenals, extirpation, 50
LANNELONGUE, thyroidectomy, 27
INDEX OF AUTHOES
549
LANNOIS, cutaneous absorption, 520
LAQUER, uric acid, 389
LAQUEUR, l.ipolytic enzyme, 119
LASSAIGNE, digestion, 154
LASSAR, albuminuria, 404
LASSAR COHN, bile acids, 143
LATIMER, ptyalinogen, 82
LATSCHEMBERGER, intestinal absorption,
287
LAXJLANIE, thyrpidectomy, 24
LAUNOY, pancreas, 89
DE LAURES, skin, absorption, 518
LAUTENBACH, liver, antitoxic function,
332
LAVERAN, intestinal bacteria, 224
LAVOISIER and SEGUIN, sweat-glands,
48
LAYCOCK, intestinal excretion, 361
LEA, SHERIDAN, pancreas, 86, 91,
93
salivary digestion, 157
LEBEDEFF and MUNK, fat absorption,
326
LEED, milk secretion, 504
LEEUWENHOEK, intestinal bacteria, 22b
LEGERT, fat, derivation, 327
LEHMANN, albuminuria, 404
milk secretion, 513
peptones, 170
LE NOBEL, acetone, urine, 402
LEO, pepsin, urine, 405
LEPINE, diabetes, 99, 319
salivary secretion, 70
LESAGE, faeces, biliverdin, 346
LESAGE and MACAIGNE, intestinal
bacteria, 225
LESSER, bladder, 461
LEUBE, albuminuria, physiological, 404
amidulin, 175
gastric enzymes, 175
LEUBUSCHER, intestinal absorption, 274
LEUCHS, ptyalin, 82
LEURET, digestion, 154
LEVEN, stomach, 188, 208
LEVY, MAX, sweat, 498
LEWANDOWSKY, adrenaline, 58
thyroid, colloid cells, 8, 12
LEWASCHEW, pancreas, 86, 87, 103
LEYDEN, jaundice, 146
LIEBERKUHN, glands of, 122
LIEBERMEISTER, thyroid, 19, 23
LIEBIG, acid sodium phosphate, urine,
379
faeces, 345
fat, carbohydrate origin, 326, 327
lactic acid, urine, 401
uric acid, 387
LIEBREICH and RUPPEL, vernix caseosa,
501
LIGALAS, bladder, absorption, 476
LIMBECK, diuresis, 433
LIMBOURG, bile, 220
LINDEBERGER, bile, 220
LINDEMANN, glomeruli, 442
urine, toxicity, 414
LINOSSIER and LANNOIS, cutaneous
absorption, 520
LITTEN, bile, 141
urine, secretion, 430
LIVERSEDGE, pancreatic diastase, zymo-
gen, 94, 97
LIVIERATO, diabetes, 320
LIVINI, parathyroids, 11
LOEB, saliva, 71, 78
LOBASSOFF, stomach, 113
LOEWI, animal proteinogenesis, 330
trypsin, 96
LOMBROSO, TL, diabetes, pancreatic,
318
faeces, fat of, 352
fat absorption, 282, 286
glycosuria, 100
intestine, reaction, 207
pancreas, 85, 103
parabiosis, 518
saliva, injection of pancreatic juice,
81
succus entericns, 125, 127, 130, 208,
222
zymogen, 94
LOMBROSO and BOLAFFIO, mammary
gland (development in pregnancy),
518
Lo MONACO, pepsin, 122
pituitary, 40
thyroidectomy, 24, 25
LONGET, saliva, 158
stomach, innervation, 197, 198
LORENZ, kidney, 455
LOSSNITZEN, intestine, 238
LOTHRINGER, pituitary, 38
LUBCKE, thyroid, colloid cells, 7
LUCHSINGER, hepatic glycogen, 309
sweat, 490, 496, 497, 498
LUCIANI, auto-digestion, 254
bile, 136
diabetes, 102, 105
faeces of fasting, 351
fats, intestinal absorption, 270, 278-
286
glycogen, hepatic, 312
glycosuria, 306
heart, 458
intestinal absorption, 276, 292
micturition, 469
saliva, 80
sebaceous glands, 502
secretin theory, 90, 111, 129, 142,
517
sodium chloride, urine, 406
spleen, pepsinogenesis, 122
thyroid, antitoxic functions, 22, 24
urine, chlorine secretion, 407, 430
urine, phosphorus, 408
LUDERITZ, intestine movements, 238
LUDOWEN.T, uric acid, 388
550
LUDWIG, bile, origin, 148
deglutition, 163.
digestion, 181
intestinal absorption, proteins, 272
intestinal movements, 248, 250
mechanical theory, secretion, 5
mechanical theory, urinary secretion,
426, 434
pancreas, 211
renal secretion, 5, 425, 429, 432
salivary secretion, 72, 74, 75
trypsin, 211
LUSCHER, deglutition, 168
LTTSENA, parathyroids, 33
thyroid, antitoxic function, 24
thyroidectomy, 17
LUSINI, bladder, absorption, 476
LUSSANA, alkaloids, 331
auto-digestion, 254
bile, entero-hepatic circulation, 140
gastric juice, 113
glycogenesis, 302
iron, 332
LUSTIG, glycosuria, 99, 306
pancreas, 99
LUTHJE, glycosuria, 314, 321, 362
LUTSCHINOFF, bile acids, 144
LUTTIG, vomiting, 196
LTJZZATTO, R., pentosuria, 403
pituitary, 40
MAASS, pituitary, 40
MACAIGNE, Bacterium coli, 225
MACDONELL, glycogen, 20, 302
MACFADYEN, intestinal bacteria, 224,
228
MACKENZIE, thyro-therapy, 28
MACWEENEY, intestinal bacteria, 224,
247
MAGENDIE, absorption, 300
deglutition, 159, 163, 166
gastric movements, 185, 188, 189, 197
vomiting, 195
MAGGIORA, intestinal bacteria, 224
MAGNUS, intestinal movements, 245
MAI RET, pituitary, 40
sweat, 495
MAISON, thyroidectomy, 24
MALERBA, succus entericus, 127
MALL, intestine, 235, 239
MALLOIZEL, saliva, reflex secretion, 71
MALPIGHI, acini, 2
corpuscles, 418
§ lands, 2
idney, 418
sweat-glands, 485
MALY, bile, digestive functions of, 218
hydrobilirubin, 398
pigments, 144
protein absorption, 288
putrefaction, 227
MANASSE, suprarenals, 55
MANCA, bile, 141
MANKOWSKI, pancreas, 87, 103
MANX, defaecation, 374
MARAZZINI, pancreas, 99, 103
MARBURG, bladder, innervation, 474
MARCACCI, albuminuria, physiological,
404
caecum, 366
MARCET, bile, internal function of, 212,
220
excretin, 346
MARCHESI, thyroidectomy, 17
MARCHETTI, halogens, 30
myxoedema, experimental, 18
MARCKWALD, absorption, intestine, 269
deglutition, 169
MARCUSE, diabetes, pancreatic, 319
MARES, uric acid, 388
MARFORI, ferratin, 332
MARIE and MARIXESCO, acromegaly,
41
MARIE and MOBIUS, thyroid and spleen,
31
MARINESCO, pituitary, 39
MARINO-ZUCO, suprarenals, 51, 55
urine, biotoxiii, 415
MARSHALL FLINT, pancreas, 87
MARTINOTTI, pancreas, 98
MASIUS, ano-spinal centre, 372
kidney, innervation, 449
stercobilin, 398
MASLOFF, bile, 212
succus entericus, 126
MASSAGLIA, eclampsia gra-vidica, 37
parathyroids, 36
MASSARI, pancreas, 87
MASSEN, liver, antitoxic functions, 335
urea, 385
MASSENTI, thyroid and spleen, 31
DI MATTEI, suprarenals, 51
MATTEI, thyroid, 31
MATTHES, auto-digestion, 257
autolytic ferments, 406
MAVROJANNIS, sweat, 495
MAXER, pancreas, 101
MAYER, R., bladder, innervatiou, 470
MAYER, S., bladder, 461
defaecation, 373
intestinal movements, 239, 248
pancreas, 104
stomach, innervation, 197
sweat, 496
MAZZIOTTI and CAPOBIANCO, parathy-
roids, 12, 33
MECKEL, pancreas, 84
suprarenals, 43, 47
MEES, urine, pepsin, 405
MEISSL and STROHMER, fat, carbo-
hydrate origin, 328
MEISSNER, creatine, 392
creatinine, 391
digestion, gastric, 173
plexus of, 233
protein absorption, 286
INDEX OF AUTHOES
551
MEISSNER, urea formation, 383
uric acid, 386
MELTZER, deglutition, 160, 162
MENDEL and MARINESCO, acromegaly,
41
MENDELDORP, Bi-unner's glands, 124
V. MERINO, absorption, gastric, 264
absorption, intestinal, 209, 270, 271
amylolytic, enzyme, liver, 305 ; pan-
creas, 209
diabetes, 314 ; pancreatic, 317, 318
diabetes, phloridzin, 316
glycogen, protein origin, 311
pancreas, 99, 209
saliva, 157
stomach, 109, 188
urine, sodium chloride, 406
v. MERING and MINKOWSKI, experi-
mental diabetes, 99
pancreatic diabetes, 317
MERLEN, myxoedema, 27
MESNIL, cutaneous absorption, 520
METT, proteolysis, 171
MEULI, thyroid, 20
MEYER, faeces of fasting, 351
kidney, 429, 457
uric acid, 387
MIESCHER, nucleins, 179
MIKULICZ, tetany, 15
MILLS, oxalic acid, urine, 400
MILNE-EDWARDS, stomach, 197
MINGAZZINI, intestinal villi, 294
MINKOWSKI, amylopsin, 208
diabetes, experimental, 99
diabetes, pancreatic, 317, 318
diabetes, phloridzin, 316
fat absorption, 281
glycosuria, 100
lactic acid, urine, 401
liver, antitoxic functions, 334
pancreas, 99, 289
protein absorption, 289
urea formation, 383, 385
uric acid, 387, 388
MINKOWSKI and NAUNYN, bile, origin
of, 148
MIQUEL, gastric juice, 180
MIRONOW, milk secretion, 515
MISLAWSKI, bladder, 474 ; intestinal
movements, 241, 248, 252
MOBIUS, thyroid, 31
MOELLER, faeces, 355
MOITESSIEK, creatinine, 393
MOLESCHOTT, bile in digestion, 217
cholesterol, 145
jaundice, 146
skin, 483
MONARI and DE FILIPPI, gastrotomy,
182
intestinal resection, 230
MONTI, R. and A., kidney, secretion,
455 ; structure, 422
villi, 297
MONTUORT, glycogenesis, 304, 311
pancreatic diabetes, 319
MOORE, chromagen, adrenals, 55
MOORE and ROCKWOOD, bile, 220
fat absorption, 284
intestine, reaction, 207
MORAT, asphyxia, 308
mastication, 166
stomach, movements, 185, 197
MORAX, ethereal sulphates, urine,
395
MOREAU, succus entericus, nervous
control, 129
MORESCHI, biological reaction, 294
MORGAGNI, bile, 136
bile salts, jaundice, 146
pyramid, 6, 8
MORITZ, pressure, 185
stomach, 188, 193
MORONI, bile, entero- hepatic circula-
tion, 140
MORPURGO, parabiosis, 518
MORUET, pancreas, 104
MOSCATELLI, acetonuria, 402
lactic acid, 401
MOSER, deglutition, 165
Mosso, deglutition, 168
oesophagus, 239
Mosso and PELLACANI, bladder, inner-
vation, 474
micturition, 464
Moussrr, parathyroids, 32, 33
thyroidectomy, birds, 19
MULDER, protein absorption, 286
MULLER, A., intestinal movements,
244
MULLER, F., faeces, 220, 350, 354 ; fast-
ing, 351 ; fat of, 352
fat absorption, 283
urobilin, 398
MULLER, J., digestion, 154
glands, 3
intestine, movements, 248
jaundice, 146
kidney, 418, 430
pancreas, 93
pepsin, 117
saliva, 158
secretion, 3, 79
stomach, innervation, 197, 198
MUNK, H., thyroidectomy, 19, 22
MUNK, I., bile, 141
fat absorption, 283, 284, 326
fat, from carbohydrates, 327
intestinal absorption, 270, 279
milk secretion, 507
urine, phosphorus, 408
urine, secretion, 430, 433
urine, sodium chloride, 407
MUNK and ROSENSTEIN, intestinal ab-
sorption, 270, 272
MiiNZER and PALMA, lactic acid, urine,
401
552
PHYSIOLOGY
MUNZEK and PALMA, phosphorus
poisoning, 410
MURATORI, storaaCh, innervation, 201
MURRAY, thyro-therapy, 28
MITRRI, urine, secretion, 430
MUSCULUS, amylolytic enzyme, liver,
305
buccal digestion, 157
intestinal digestion, 209
pancreas, saccharifying ferment, 209
urine, reaction, 380
MYA, urobilin, 399
MYA and BONFANTI, pepsin, urine, 405
NABARRO, suprarenals, 55
NASSE, amidnliu, 157, 175
glycogenesis, 303 ; muscular, 310
intestinal movements, 239, 248
lipolytic digestion, stomach, 175
NAUNYN, bile, origin, 148
glucose, 316
uric acid, 387
NAWROCKI, bladder, 471, 475
sweat, 497
NEBELTHAN, lactic acid, iirine, 401
NENCKI, bile, digestive function, 219
glycocoll, 384
intestinal bacteria, 224, 226, 227, 228
intestinal digestion, 221
liver, antitoxic functions, 335
proteins, intestinal absorption, 287
steapsin, 97
urea, 384, 385
NENCKI and ZALESKI, ammonia content
of blood, 336
intestine, reaction, 207
NEPVEU, anuria, 453
NEUBAUER, urine, ammonia, 409
urine, creatinine, 391
urine, oxalic acid, 400
urine, sulphates, 407
NEUJEAN, adrenaline, metabolism, 62
NEUMANN, cutaneous absorption, 520
NEUMEISTER, bile, action on fat absorp-
tion, 220
digestive products, 173
erepsin, 293
glycogenesis, 303
mammary gland, 502
neurine, adrenals, 56
peptone, 289, 290, 293, 329
protein, intestinal absorption, 289
NEUMEISTER and MALTHES, thyroid, 30
NICATI and RIETSCH, gastric juice, 180
NICOLAS, faeces, 359
thyroidectomy, 19
NIEBEL, lactase, 127
NOLF, saliva, freezing-point, 81
v. NOORDEN, glycosuria, 309
NOTHNAGEL, adrenals, 51
intestinal movements, 363
NOTKIN, thyreo-gummin, '29
thyreo-protein, 29
Novi, bile, iron content, 145
saliva, rate of secretion, 80
NUSSBAUM, bladder, innervation, 471,
475
urine, secretion, 439, 455
O'BEIRNE, defaecation, 369
OBERMAYER, skin, 520
ODDI, bile-duct, 214
gall-bladder, 214
gastric digestion, 172
glycosuria, 306
OEHL, saliva, 82, 83
skin, 482
stomach, innervation, 198
sulphocyanide, saliva, 82
vesical nerves, 471
OFFER, pancreas, 101
OGATA, digestion, 181
lipolytic enzymes, 118, 174
trypsin, 211
OIDTMANN, pancreas, analysis, 95
OLIVER, neurine, suprarenals, 56 ;
adrenaline, 58 ; medullary juice,
61
ONORATO, kidney, functions, 444
urine, biotoxin, 415
v. OPENCHOWSKI, intestine, movements,
241
stomach, innervation, 192, 198
vomiting, 196, 201
OPIE, pancreas, 87, 102
ORBAN, lactase, 127
ORD, myxoedema, 14
ORE, bile, 141
ORECCHIA, thyroidectomy, 19
ORFILA, liver, antitoxic functions,
332
OSBORNE, pituitary, 41
OSLER, bile, 141
OSTRUMOW, sweat, 496
OSTWALD, urine, reaction, 380
v. OTT, defaecation, 373
intestinal movements, 250, 252
peptone, regeneration, 292
phosphorus, urine, 409
sweat, 497
OTTE, auto-digestion, 259
OTTO, glucose of blood, 299
OVERBECK, urine, secretion, 430
OWSJANNIKOW, saliva, reflex secretion,
70
PACE, uric acid, 388, 389
PACHON, stomach, 181
PADERI, glycosuria, 318
PAL, adrenals, excision, 51 ; adrenaline,
59
glycaemia, 320
intestinal movements, 237
PALADINO, caecal digestion, 365
salivary glands, innervation, 70
PALMA, urine, lactic acid, 401
INDEX OF AUTHOES
553
PANETH, kidney, 429, 434
PANUM, auto-digestion, 254
PARISET, pancreatic diabetes, 319
PARISOT, skin, absorption, 519
PARKES, urine analysis, 381
PARTSCH, milk, 509
PASCHELES, electrical endosmosis, 520
PASCHUTIN, steapsin, 97
succus entericus, 213
PASCUCCI, spleen in digestion, 175
PATELLA, albuminuria, 405
PATON, NOEL, bile, 135, 138
glycogenesis, 304, 305
suprarenal diabetes, 60
PATRY, vomiting, 196
PATTA, adrenaline, 58
adrenaline, metabolism, 62
PAUTYNSKI, urine, secretion, 438
PAVY, auto-digestion, 253
amylolytic enzyme, liver, 304, 305
glycogenesis, 302, 306, 308
glycosuria, 306
PAWLOW, ammonia content of blood,
360
bile in digestion, 219
enterokinase, 209
gastric juice, 109, 114, 115
kidney, 432
liver, antitoxic functions, 335
pancreas, 89, 99
pancreatic juice, 95, 209
saliva, 70 ; psychical secretion, 71
stomach pouch, 111, 114
PAWLOW and SCHUMOWA - SIMANOW-
SKAIA, gastric glands, 108
PECQUET, lacteals, 269
PEKELHAKING, gastric juice, 113
PELLACANI, bladder, 474
micturition, 464
PENCE, pancreas, 103
PENSA, kidney, 452
PEPERE, eclampsia gravidiea, 37
PERDisGEATand TRIBONDEAU, pancreas,
86
PEREWOZNIKOFF, fat absorption, 278
PEROSINO, suprarenals, 49
PERRONCITO, gastric juice, 180
PESCI and ANDRES, cutaneous absorp-
tion, 521
PETTENKOFER, bile acids, 145
fat of protein, 327
PETTENKOFER and VOIT, fats, intestinal
absorption, 323
metabolism, 488
milk, 507
nitrogen, faeces, 350
protein "sparers," 507
FETTERS, acetone, urine, 402
PETTIT, pepsin, 117
suprarenals, 54
PEYER, glands, 2
PEZZOLINI, suprarenals, 57 ; medullary
extract, 61
PFAFF, kidneys, 445
PFALZ, bladder, automatic rhythm, 475
PFAUNDLER, suprarenals, 47
PFEIFFER and LEED, human milk, 504
peptone, 288
PFISTER, genito-mammary relations, 517
PFLUGER, carbonic acid, urine, 409
diabetes, 99, 319
fat, protein origin, 327
fats, intestinal absorption, 282
glycogenesis, 311, 321
glucose, 299
hepatic glycogen, 302, 308
intestinal movements, 248
liver, 131
pancreas, 85
PFUNGEN, stomach, contractions, 185
PHILIPPEAUX, suprarenals, 49
PHISALIX, parathyroids, 32
thyroidectomy, 19
PIANTONI, milk, 508
PICK, adrenal extract, 58
PIERINI, skin, absorption, 519, 520,
521
PINELES, parathyroids, 37
PISENTI, pituitary, 38
urine, secretion, 436
PITCAIRN, digestion, 153
PLANER, carbonic acid, urine, 409
gases, stomach and intestine, 347
PLOSZ, protein absorption, 288
POLL, phaeochrome, 45
suprarenals, 53
POLLITZER, protein absorption, 288,
290
PONFICK, kidney, 432
PONSGEN, stomach, movements, 185
POPIELSKI, secretin theory, 91
POPOFF, peptone regeneration, 292
POPPER, colostrum corpuscles, 512
PORCHER, milk, 508
PORTIER, bile, 142
lactase, 127
POSNER, haematogenous albuminuria,
404
urine, 476
POSTEMPSKI, stomach, 113
POUSSON and LIGALAS, bladder absorp-
tion, 476
PRAUSNITZ, faeces, 355, 356
PREGL, amylolytic enzyme, liver, 305
succus entericus, 127, 292
PRENANT and FUSARI, parathyroids,
11
PREVOST, deglutition, 167
nephrectomy, 410
PRIMAVERA, uroerythrin, 399
PROTOPOPOW, ureters, 459
PROUT, hydrochloric acid, gastric juice,
115
PUGLIESE, thyro-iodine, 30
PUGNAT, pancreas, 87
PURKINJE, sweat-glands, 485
554
PHYSIOLOGY
QUEIRDLO, sweat, 495
QUINCKE, protein, succus entericus, 292
succus entericus,- 222
urobilin, 399
RADZIEJEWSKI, intestinal movements,
238
RANKE, bile, 135
creatine, toxicity, 413
RANVIER, fats, intestinal absorption,
279
RAWITSCH, stomach, innervation, 197
RE ALE, ethereal sulphates, urine, 396
pentosuria, 403
uroerythrin, 399
REALE and BOERI, ammonia, urine, 410
oxalic acid, urine, 401
REAUMUR, digestion, 153, 170
gastric juice, 170
REES, absorption, 273
REHFISCH, micturition, 466 ; vesical
innervation, 413; vesical sphincters,
463
REID, cutaneous absorption. 521
REISET, milk secretion, 513
REITMANN, pancreas, 103
REMAK, stomach, 108
RENAUT, pancreas, 87
RENAUT and LAGUESSE, pancreas, 85
REUTER, intestinal villi, 297
REVERDIN, myxoedema, 13, 19
thyroidectomy, 13, 19, 20
v. RHORER, urine, secretion, 435
v. RHYNBERK, pituitary, 40
RIBBERT, mammary gland, 517
urine, secretion, 440
RICHET, gastric juice, 116
stomach, 108
RIEDER, faeces, 350
RIESS, lactic acid, urine, 401
uric acid, 387
RIETSCH, cholera bacillus, and gastric
juice, 180
RITTER, urine, toxicity, 411 ; hepatic
glycogenesis, 302
RIVA, bilinogen, 398
urobilin, 397, 398
urochrome, 397
uroerythrin, 399
RIVINI, glands, 2
ROBERTS, amylopsin, 208
ROCKWOOD, bile, 220
fat absorption, 284
intestine, reaction, 207
ROGER, liver, antitoxic functions, 332,
334
ROGOWITSCH, pituitary, 39, 41
thyroid, antitoxic function, 24
ROHMANN, glucase, 97
fat absorption, 283
fat of faeces, 220
succus entericus, 213
ROHRIG, bile, 141, 220
ROHRIG, cutaneous absorption, iodine,
520
lacteals, 270
milk, innervation, 514
sweat, 495
ROLLESTON, suprarenals, 47
RONA, glycogenesis, 304
ROSENBERG, pancreas, 101, 282
ROSENFELD, fat absorption, 326
ROSENSTEIN, absorption, 270
ROSENTHAL, bladder, sphincters, 461
v. ROSEN, stomach, innervation, 198
Ross, thyro-iodine, 30
ROSSBACH, sweat, 498
Rossi, intestine, reaction, 208
pancreas, 87
thyroidectomy, 25
ROSSONI, hysterical anuria, 361, 453
ROSTER, urea formation, 383
ROUELLE, urine, composition, 378
ROWE, stomach, 194, 198
ROUXEAU, parathyroids, 32
ROVIGHI, ethereal sulphates, urine, 395
ROWLAND, spleen, 122
ROY, oncograph, 447
RUBNER, creatine, 392
faeces, 351
fat, carbohydrate origin, 328
RUDBECK, lacteals, 269
RUGE, gases, intestinal, 348
RUGGI, resection, intestine, 230, 269
RUPPEL, vernix caseosa, 501
RUSH, thyroid, 19
Russo-GiLiBERTi, stomach, innervation,
197
suprarenals, 51
RUYSCH, glands, 2
kidney, 418
SABBATANI, intestine, 235
SACCHI, pituitary, 39
thyroidectomy, 19
SACHS, sugar derived from fat, 312
SAGGINI, metabolism, 231
SAHLI, urine, pepsin, 405
urine, trypsin, 405
SAILLET, urobilinogen, 398
SALKOWSKI, amylolytic enzyme, liver,
305
autolytic cleavage products, 406
hypochloruria, 407
intestinal putrefaction, 226
peptones, 289, 290
pentosuria, 403
phenaceturic acid, 395
protein cleavage, 384
urea, 384, 385
urine, neutral sulphur, 407
SALOMON, hippuric acid, 394
intestinal putrefaction, 226
liver, antitoxic functions, 334
urea, 385
uric acid, 386
INDEX OF AUTHOES
555
SALVIOLI, intestinal movements, 240,
245
SALVIOLI, peptone synthesis, 290, 293
suprarenal extract, 57, 58 ; medullary
extract, 61
SANARELLI, intestinal bacteria, 225
SANDERS, bile absorption, jaundice, 143,
146
SANDEKS-EZN, intestinal movements,
234
SANDMEYER, diabetes, 100
glycosuria, 318
pancreas, 100
SANDRAS, amylopsin, 97
SANDSTROM, parathyroids, 9, 32
SANOTZSKY, stomach, 108, 111
SAKQUIRICO and CANALIS, thyroid-
ectomy, 21, 24, 131
SANQUIRICO and ORECCHIA, thyroid-
ectomy, 19
SANSON, hepatic glycogenesis, 301
SANTORIO, perspiration, 487
SAUER, kidney, secretion, 455
kidney, structure, 422
SAUERBECK, pancreas, 103
SAVIOTTI, pancreas, 85
SAWJAWLOW, plastein, 174
SCHAFER, adipose tissue, 324
intestinal absorption, 124
intestinal villi, 266
mammary gland, 510
neurine, adrenals, 56
pancreas, 102
pituitary, 40
suprarenals, 56, 58 ; medullary ex-
tract, 61
sweat-glands, 485
SCHARDINGER, intestinal bacteria, 224
SCHEELE and BEKGMANN, urine, com-
position, 378
SCHERER, urine, reaction, 379
SCHIERBECK, sweat, 489, 493
sweat C02 secretion, 493
SCHIFF, M., alkaloids, 331
auto-digestion, 254
bile, entero-hepatic circulation, 140,
141
deglutition, 168
glycogenesis, 300, 302, 306
glycosuria, 306
intestinal movements, 248, 252
lipase, 127
liver, 300
pancreas, 99
propepsin, 120
saliva, 158
salivary glands, 76
stomach, 108, 188, 189, 191, 197
succus entericus, 127, 228
suprarenals, 51, 58
thyroidectomy, 13, 16, 19, 20, 31
thyroid grafts, 27
vomiting, 196
SCHIFF, U., cholesterol, 145
SCHIFFER, creatinine, toxicity, 413
SCHILD, intestinal bacteria, 224
SCHILLBACH, intestinal movements, 238
SCHILLING, urine, secretion, 441
SCHLANGE, intestine, 230
SCHLATTER, gastrotomy, 182
SCHMIDT, A., bile, intestinal function,
219
gastric juice, 118
stomach, 108, 154, 197
thyroidectomy, 14
uric acid, kidneys, 437
SCHMIDT, C., diabetes, 320
digestion, 154
gastric juice, 115, 116
intestinal absorption, 273
SCHMIDT, pancreas, 103
SCHMIDT-MULHEIM, digestion, 179, 221
intestinal absorption, 270, 272, 289
peptone, 173, 289
SCHMIEDEBERG, ammonia, urine, 285,
410
glycuronic acid, 403
hippuric acid, 393
urea, 385
SCHMULEWITSCH, bile, 141
cellulose, pancreatic digestion, 226
pancreas, 226
pancreatic juice, 209
SCHNEIDER, mucous membrane, 2
SCHONEMANN, pituitary, 40
SCHOTTELIUS, intestinal bacteria, 226
SCHOTTEN, cholalic acid, 143
SCHOTTIN, sweat, 490, 491
SCHREGER, thyroid, 19, 23
SCHREITER, deglutition, 166
v. SCHRODER, digestion, 178
liver, antitoxic functions, 334
urea, toxicity, 411
urea formation, 383, 385
uric acid, 387
SCHRODER VAN DER KOLK, mastication,
156
SCHUCHARDT, gastrotomy, 182
SCHULE, gastric glands, 110
SCHULTZE, W., pancreas, 87, 103
SCHULTZE, pituitary, 41
SCHULTZEN, oxalic acid, 400
urea, 384
SCHULTZEN and RIESS, lactic acid, urine,
401
SCHUMBERG, chymosin, 118
SCHUMOWA - SIMANOWSKAIA, gastric
glands, 108
gastric juice, 115, 292
peptones, intestinal conversion, 292
SCHUPBACH, intestinal movements, 237
SCHUPFER and MAGNANIMI, liver, anti-
toxic functions, 334
SCHUR, purine, 390
SCHUTZ, law, 171, 211
pepsin, 171
556
PHYSIOLOGY
SCHUTZ, stomach, movements, 185, 189,
197
SCHWANN, bile, intestinal function, 219
cell theory, 4
digestion, 153, 154
gastric juice, 117
liver, 135
pepsin, 117
SCHWARTZ, stomach, 185
vomiting, 195, 196
SCIOLLA, cutaneous absorption, 520
SCOTTI, intestinal absorption, 282
SEEGEN, glycogenesis, 303
pancreas, 98
protein origin, 311, 312
SEGALAS, liver, 300
urine, secretion, 433
SEGUIN, sweat-glands, 487
SEIFFERT, suckling, 505
SELMI, gastric juice, 118
ptomaines, 359
SENATOR, pepsin, urine, 405
urine, secretion, 429, 433
uric acid, 387
SENN, intestine, 229
pancreas, 98
SERRANO, myxoedema, 27
SHERRINGTON, anal sphincter, 373 ;
bladder, innervation, 474
SHORE, peptone, 289, 290, 291
SICK, thyroidectomy, 14
SIEBER, gastric juice, 180
intestinal bacteria, 224, 228
SIMON, bile, secretion, 141
milk, human, 507
SIMON and REES, intestinal absorption,
273
SISTO, lactase, J28
SKABITSCHEWSKI, bladder, 471, 475
SLOSSE, thyroid juice, 29
v. SOBIERANSKI, urine, secretion, 438
SOETBEER, gastric glands, 110
SOKOWIX, bladder, innervation, 471, 475
SOLERA, saliva, 83
SOMMERING, pancreas, 84
SONSINO, pancreas, 97
SPALLANZANI, auto-digestion, 253
digestion, 153, 170
gastric juice, 117, 179
stomach, 185, 189
SPALLITTA, kidney, secretion, 453, 454
SPARAPANI, eclampsia gravidica, 37
SPIESS, saliva, 74
SPIRO, K., physiological selection, 276,
443
SPIRO, N., bile, 136 ; nitrogen content,
147
urine, lactic acid, 401
SPITZER, pancreas, analysis, 94
SSOBOLEW, pancreas, 103
SSUBOTIN, milk, 507, 508
STADE, lypolysis, 174
STADELER, phenol, urine, 395
STADELMANN, pepsin, urine, 405
STARLING, defaecation, 369
hormone theory, 90, 111
law of intestine, 243
mammary gland, 517
mechanism of secretion, 90
movements of intestine, 239, 240, 244,
249, 250 ; of large intestine, 369
secretin theory, 90, 111, 129, 142,
517
polyuria, 452
STEFANI, renal secretion, diuresis, 434
STEINHAUS, milk, 511
STENSEN, glands, 2
sweat-glands, 485
STERN, bile pigments, 148
ureters, 459
STICH, faeces, 358
STIEDA, pituitary, 40
STILLING, suprarenals, 53
STOHMANN, methane, 348
STOHR, stomach, 107
STOKES, albuminuria, 404
STOKVIS, hippuric acid, 394
STOLNIKOW, Eck's fistula, 335
STOORBE, cutaneous absorption, 520
STRADIVIRI, eclampsia gravidica, 37
STRASSBURGER, urine, carbonic acid, 409
STRAUSS, sweat, 495
STREEKER, creatine, synthesis, 392
STRICKER, saliva, 158
STROHMER, fat, carbohydrate origin, 238
STRUMPELL, acromegaly, 41
Graves' disease, 28
SURMONT, liver, antitoxic functions, 334
SUTO, fat absorption, 271
v. SWIETEN, jaundice, 146
vomiting, 235
SYMPSON, diabetes, glycolytic enzyme,
319
SzAB6, milk, 511
SZYMONOWICZ, mammary gland, 511
pituitary, 40
suprarenals, 50, 57
TAKAMINE, adrenaline, 59, 60
TALMUD, mammary gland, 503
TANTINI, vomiting, 195
TAPPEINER, intestine, bacteria, 226
intestine, gases, 348
TARCHANOFF, bile, 140
TARULLI, spleen, digestion, 175
spleen, pepsin, 122
urine, trypsin, 405
TENNESON, anuria, 453
TERRAY, oxalic acid, urine, 401
THALER, eclampsia gravidica, 37
THEUVENY, parathyroids, 36
THIERFELDER, milk, 511
THIROLOIX, pancreas, 100
THIRY, succus entericus, 222
succus entericus, nervous control, 127,
128
INDEX OF AUTHOES
557
THIRY, succus entericus, protein con-
tent, 292
THOMSON, ALLEN, intestine, 368
stomach, 184
suprarenals, 42
THUDICHUM, urochrome, 397
TIBERTI, pancreas, 103
TIEDEMANN, absorption, 300
digestion, 154
intestine, 365
TIZZONI, adrenals, 51
TizzoNi-and CENTANNI, pituitary, 40
thyroidectomy, myxoedema, 18
TIZZONI and FILETI, thyroidectomy,
rabbit, 19
thyroid and spleen, relations, 31
TOPFER, thyro-iodine, 30
TORNIER, kidney, 455
TOURTON, sweat, 490
TOURTUAL, deglutition, 163
TRAMBUSTI, kidney, secretion, 455
TRAUBE-MENGARINI, cutaneous absorp-
tion, 521
TRIBONDEAU, pancreas, 86
TRICOMI. gastrotomy, 182
TROMBELTA, intestine, 230
TRUMPY and LUCHSINGER, sweat, 490,
498
TRZEBICKY, intestine, 229
TSCHERWINSKY, fat, carbohydrate origin,
327
TSCHLENOFF, urea, 383
TUCZEK, saliva, 82
TUMAS, vomiting, centre for, 201,
202
v. UDRANSKY, intestinal bacteria, 228
UFFELMANN, gastric juice, 116
UGHETTI, thyroid, 17, 31
UHLE, urea, 383
USTIMOWITSCH, urine, secretion, 428,
433
VAILLARD, pancreas, 99
VALENTI, gastric innervation, 200
VALENTIN, amylopsin, 97
bladder, 474
deglutition, 168
digestion, 154
intestinal movements, 248, 252
micturition, 469
VALENTOWICZ, milk secretion, 515
VALISNIEKI, digestion, 153
VANDERLINGEN, eclampsia gravidica,
37
VANDEVELDE, bile, 212
trypsin, 210
VANLAIR, stercobilin, 398
VANNI, kidney, circulation, 449
VAN RHYNBERK, pituitary, 40
VASSALE, pancreas, 87, 103
paragangline, 59, 60, 61
parathyroids, 11, 35, 36
VASSALE, sebaceous glands, 501
suprarenals, 52, 54, 58, 61
thyroids, 11, 19, 23, 28, 30
VASSALE and GENERALI, parathyroids,
10, 32
VASSALE and Rossi, thyroidectomy, 25
VASSALE and SACCHI, pituitary, 39, 40
VAUQUELIN, urine, 378
VEJNX TYRODE, kidney, 445
VELICH, adrenal extract, 57, 58
VELLA, succus entericus, 126, 127, 212
VERDELLI, albuminuria, 404
VERHOOGEN, liver, antitoxic functions,
333
VERSARI, vesical sphincters, 461, 464
VESTRAETEN, eclampsia gravidica, 37
VIAULT and JOLYET, internal defaeca-
tion, 364
VICARELLI, eclampsia gravidica, 37
lactic acid, urine, 401
VIERORDT, liver, 131
urinary pigments, 397
ViGAN6, biological reaction, 294
VIGNAL, intestinal bacteria, 224
VILLE, fat absorption, 282, 283
VILLETTI, liver, antitoxic functions, 334
VINCENT, SWALE, adrenals, chromaffine
tissue, 54
chromaffine extract, 61
pituitary extract, 40
VINCI, anuria, 453
VIOLA, pituitary, 38
VIOLA and BICKEL, urine, toxicity,
414
VIOLA and GASPARDI, auto-digestion,
256
VIRCHOW, auto-digestion, 254
VIRIDET, digestion, 153
VISENTINI, pancreas, 101, 103
VIZIOLI, intestinal bacteria, 228
VOGEL, digestion, 154
VOIT, C., cutaneous absorption, 520
faeces, 220, 345, 349, 354
fat absorption, 283, 323
fat from protein, 327, 507
hepatic glycogen, 309
peptone, conversion, 293
protein, absorption, 286, 288, 293
protein "sparers," 327
uric acid, 387
urine, reaction, 379, 387
VOIT, E., glycogen, liver and muscle,
310, 311 ; in hibernation, 312
VOIT, F., faeces, 354
VOIT and BAUER, intestinal absorption,
273
protein absorption, 287
VOIT and MEISSNER, creatinine, 391
VOLHARD, creatine, synthesis, 392
lipolytic enzyme, 118, 174
pancreas, 89
VULPIAN, chromogen, adrenals, 55
hysterical oliguria, 454
558
PHYSIOLOGY
VTTLPIAX, oxalic acid, urine, 401
sweat, 497, 498
WAKEMAX, diabetes, suprarenal, 60
WALKER, stercobilin, 346
WALKOWITSCH, tetanv, 15
WALLER, A., deglutition, 167
WALLER, A. D., intestinal villi, 268
skin absorption, 521
WALRAWEXS, renal circulation, 449
WASILEWSKI, pepsin, urine, 405
WASsiLiEFF, deglutition, 167, 168, 169
WASSMAXX, digestion, 154
pepsin, 117
WEBER, E., intestine, movements, 250
WEDEXSKI, urine, animal gum, 402
WEINLAXD, auto-digestion, 260
WEIXTRAUD, uric acid, 389
WEISS, glycogenesis, 304
glycogen, protein origin, 311
tetany, 15
WELSH, parathyroidectomy, 33
WEXDT, sweat glands, 485
WENZ, succus entericus, 127
WEPFER, digestion, 153
gastric movements, 185
WERTHEIMER, bile, 140
WHARTON, glands, 2
WIESXER, carbohydrates, origin from
fat, 313
WIEZEL, chromaffine extract, 61
suprarenals ; 53, extract, 57
WILL, fat absorption, 278
v. WILLEBRAND, cutaneous excretion,
494
WIXKLER, ileo-caecal valve, 371
WINTER, urine, 380 ; isotouia, 407
WIXTERXITZ, cutaneous absorption, 519,
521
WIRSUNG, glands, 2
WITTE, peptone, 174
v. WITTICH, amylolytic enzyme, liver,
304
bile, 212
pepsin, 117
v. AVITTICH, urea, 437
vesical sphincters, 461
WLASSOFF, bladder, 473
WOHLER, hippuric acid, synthesis, 393
oxalie acid, 401
urea, synthesis, 382, 386
uric acid, 387
WOLFF, intestinal movements, 247
WOLFLER, thyroidectomy, 16
WORMSER, thyro-iodine, 30
WROBLEWSKI, gastrotomy, 182
WULFF, nitrogen of purines, 389
WUXDT, bladder, mucous membrane, 476
WURTZ, intestinal absorption, 272
YANASE, intestinal movements, 37, 242
parathyroids, 37
Yvox, urea, 383
ZABELIX, uric acid, 387
ZAGARI and PACE, uric acid, 388, 389
ZAITSCHEK, faeces, nitrogen, 351
ZALESKI, intestine, reaction, 207
liver, antitoxic functions, 336
ZAMBONI, pancreas, 99
ZAMSHIX, ureters, 459
ZAXDA, thyroidectomy, 24, 31
ZAXFROGNIXI, eclampsia gravidica, 37
suprarenals, 52, 54
ZATSCH, hepatic glycogen, 310
ZAWADSKY, pancreatic juice, 95
ZAWILSKI, lacteals, 270
v. ZEISSL, bladder, 466, 472, 474, 475
ZILLESSEX, lactic acid, urine, 401
ZIMMERMANX, buccal digestion, 157
ZOJA, faeces, fat of, 352
urobilin, 398
ZUCKERKANDL, abdominal paraganglion
45
ZULZER, diabetes, suprarenal, 60
pancreas, 101
ZUXTZ, pancreas, 104
protein absorption, 288
ZWAARDEMAKER, deglutition, 166
ZWEIFEL, pancreas, 97
END OF VOL. II
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